Mitochondrial dysfunction in diabetic kidney disease is compartment and stage specific, reflecting differences in renal cell metabolism, function, and injury response. This article introduces a framework for interpreting mitochondrial dysfunction across renal cell types and disease stages. Proximal tubular stress progresses from increased transport demand to mitochondrial injury and impaired quality control. Distal nephron, immune, and interstitial mitochondrial mechanisms remain incompletely defined. In glomerular endothelial cells and podocytes, mitochondria primarily regulate stress and injury signaling. Cell-specific mitochondrial phenotyping may reveal reversible pathways and guide more precise therapeutic strategies in diabetic kidney disease.

Diabetes subtype-specific research is challenging when using data from large registers, and validation studies of Swedish National Diabetes Register (NDR) diagnoses remain limited. We aimed to develop an algorithm to classify diabetes subtypes using linked longitudinal data, compare with NDR, and validate it using polygenic risk scores. We developed an algorithm that reliably distinguishes diabetes subtypes with higher granularity compared with NDR and is validated by polygenic risk scores. Our algorithm reveals clinically meaningful heterogeneity that may be overlooked in registers and enables subtype-specific diabetes research.

We undertook this study to define how fat consumed before oral glucose attenuates postchallenge glycemia. We asked whether olive oil reduces glycemia by slowing gastric emptying and investigated contributing endocrine and neural pathways. Olive oil increased glucagon, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1; slowed gastric emptying; and reduced early glycemia in mice. Glucagon and glucagon-like peptide-1 signaling acted redundantly, with vagal involvement. Nutrient timing integrates endocrine-neural regulation of gastric emptying and glycemia, supporting evaluation of meal sequencing in humans.

Although monocytes can accumulate lipids, whether diabetes alters monocyte lipid loading is unknown. Nonclassical monocytes accumulate more lipids via a process that is partly regulated by hyperglycemia in people with diabetes and in three different mouse models of diabetes. Increased lipid loading promotes a more activated monocyte phenotype. Nonclassical monocytes contribute to the accumulation of foamy kidney macrophages in a mouse model of diabetic kidney disease.

Loss of YME1L promotes podocyte senescence in diabetic kidney disease. YME1L deficiency induces sustained maladaptive integrated stress response activation. YME1L interacts with and regulates mitochondrial GRP75 homeostasis. GRP75 accumulation drives persistent integrated stress response activation and mitochondrial dysfunction.

The effects of 16 ABCC8 variants, previously reported in heterozygous association with maturity-onset diabetes of the young (MODY), some with prior diagnosis of hypersinulinism, were assessed in recombinant Kir6.2/SUR1 KATP channels. Thirteen of 16 variants cause loss-of-function, 3 of 16 have no effect on channel activity, and none causes channel gain of function. In conclusion, KATP loss of function is associated with later-onset diabetes. Any presumption that MODY-associated ABCC8 variants must induce KATP (gain of function) and that KATP inhibitors are appropriate treatment is therefore inaccurate.

The role of endogenous opioid signaling within pancreatic islets remains poorly defined. We investigated whether dynorphin A regulates insulin secretion and characterized the receptor requirements for the acute response to applied dynorphin A in mouse and human islets. Applied dynorphin A suppressed glucose-stimulated insulin secretion by remodeling β-cell Ca2+ oscillations through an opioid receptor-dependent, Na+/K+-ATPase-associated pathway. This response required μ-opioid receptors in mouse β-cells and was pharmacologically consistent with δ-opioid receptor involvement in human islets, defining species-dependent receptor mechanisms for the acute response to dynorphin A.

We undertook this study because albuminuria and estimated glomerular filtration rate often identify diabetic kidney disease risk only after substantial kidney injury in type 1 diabetes. We asked whether blood DNA methylation patterns could predict future DKD progression and improve clinical risk stratification. Genome-wide leukocyte methylation sequencing identified hypomethylated regions and a four-locus methylation risk score (SLC4A4, FSTL4, ICA1, and PTK2) that improved prediction beyond clinical risk models and was validated in 330 participants. Podocyte multiomics showed concordant hyperglycemia-induced hypomethylation and gene activation, supporting the biological plausibility of the blood-derived risk score.

Cotransplantation of allogeneic islets with microgels coated with streptavidin fused with Fas ligand and protease-resistant CXCL12 results in robust and sustained diabetes reversal for over 6 months in streptozotocin-induced diabetic mice and induces local immunomodulation, enhances Treg recruitment within the graft, and improves graft vascularization. This study addresses a critical challenge in cell transplantation, namely the need to develop technologies that enable local immunoprotection of the graft while eliminating the need for systemic immunosuppression. This combination microgel technology could offer a more favorable risk-benefit profile by reducing infection risks, organ toxicity, and tumorgenicity associated with the use of systemic immunosuppression. This novel combinatory immune modulatory approach is feasible and achieves anatomic site-specific immune protection while supporting long-term islet graft function without systemic immune suppression.

Diabetic kidney disease remains progressive in many patients despite modern cardiorenal therapies, suggesting that additional persistent cell fate pathways sustain kidney injury. An unresolved question is how nutrient-derived signals determine whether renal cells undergo adaptive repair or maladaptive senescence-like dysfunction. Amino acid flux, mitophagy, lipid routing, redox balance, endoplasmic reticulum proteostasis, and inflammatory danger signaling may form nutrient-sensitive senescence checkpoints in diabetic kidney disease. Distinguishing cell cycle arrest in proliferative cells from composite senescence-like injury in postmitotic cells may improve biomarker-based patient stratification and guide metabolism-informed senescence-targeted therapies.

Insulin resistance is conventionally framed as a pathological defect in insulin action that contributes to type 2 diabetes and related metabolic disease and should therefore be identified and reversed. The comprehensive review by Gastaldelli and colleagues highlights a more complicated reality: insulin resistance is heterogeneous between individuals, tissues, pathways, and physiological states. I argue that this heterogeneity exposes a fundamental issue-insulin resistance is a phenotype, not a mechanism. It can arise through many molecular routes, occur in both disease and normal physiology, originate in different tissues, and long precede overt disease. I propose an "insulin resistance mosaic" in which its clinical significance depends on why and where insulin resistance develops, physiological compensation, environmental exposure, and end-organ vulnerability. Similar degrees of insulin resistance could therefore lead to very different clinical outcomes, remain compensated for decades, or even, in some contexts, be protective. This framework challenges the assumption that insulin resistance represents a single disease process that should invariably be overcome. Instead, we should determine why it has developed, where it resides, what it predicts, and whether modifying it improves clinical outcomes.

Insulin resistance is a hallmark of type 2 diabetes and several other metabolic diseases. However, efforts to improve insulin resistance are hindered by the biological complexity inherent to insulin action, as well as conceptual and methodological limitations to date. In September 2025, the editors of Diabetes, Diabetes Care, and Diabetologia convened an Expert Forum in advance of the 61st Annual Meeting of the European Association for the Study of Diabetes (EASD). Participants reviewed the latest research, clarified key concepts, and recommended future research priorities. Their insights were presented at a symposium during the EASD meeting and are offered in more detail here. The authors challenge the historical view of insulin resistance as a single, uniform pathophysiological condition, describing it instead as a diverse and highly plastic set of adaptive, maladaptive, acute, and chronic responses that manifest differently throughout the body, in numerous biological processes, within and among individuals, and under various physiological and environmental conditions. They describe existing methods of measuring whole-body and tissue-specific insulin resistance and offer a primer on the two main insulin signaling networks. Next, they review current therapeutic options, which offer mostly indirect effects on insulin resistance, and highlight promising strategies to inform the eventual development of true insulin-sensitizing agents. The authors call for continued investigation of the complex factors accounting for variability in insulin resistance, as well as pathway-specific defects, with the ultimate goal of developing targeted and more effective therapies for type 2 diabetes and the broader spectrum of cardiometabolic complications and related comorbidities.