About

C. Ronald Kahn is the Mary K. Iacocca Professor of Medicine at Harvard Medical School and the Chief Academic Officer and Head of the Section on Integrative Physiology and Metabolism at Joslin Diabetes Center. He is a world-recognized expert in diabetes and obesity, with a focus on insulin signal transduction and mechanisms of altered signaling in diabetes and metabolic disease. Dr. Kahn has served as Research Director of Joslin from 1981 to 2000 and as President from 2000 through 2007. He has received more than 70 awards and honors, including the Wolf Prize in Medicine, the Kober Medal of the American Academy of Pediatrics, and the highest honors of the American Diabetes Association, U.S. and British Endocrine Societies, Juvenile Diabetes Research Foundation, European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists. He has been elected to the National Academy of Science and the National Academy of Medicine. Dr. Kahn has authored more than 700 original publications and 200 reviews and chapters, contributing significantly to the fields of diabetes, endocrinology, obesity, and metabolism.

Research topics

• Biology
• Endocrinology
• Medicine
• Biochemistry
• Cell biology
• Genetics
• Internal medicine
• Computational biology
• Gerontology
• Chemistry
• Bioinformatics
• Anatomy
• Psychiatry

Selected publications

• Effect of Marked Weight Loss on Adipose Tissue Biology in People With Obesity and Type 2 Diabetes

  Diabetes Care · 2025-04-10 · 15 citations

  article

  OBJECTIVE: Weight loss improves insulin sensitivity in people with obesity and type 2 diabetes. However, the mechanisms responsible for this effect are unclear. We hypothesized that alterations in adipose tissue biology and adipose tissue-related factors in plasma are involved in mediating the systemic metabolic benefits of weight loss. RESEARCH DESIGN AND METHODS: We evaluated blood and adipose tissue samples obtained from 10 adults with obesity and type 2 diabetes before and after marked (16-20%) weight loss and >50% increase in whole-body insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure. RESULTS: Weight loss 1) decreased adipose tissue expression of genes related to extracellular matrix remodeling; 2) decreased adipose tissue expression of SERPINE 1, which encodes plasminogen activator inhibitor 1 (PAI-1); 3) did not decrease adipose tissue immune cell content or expression of genes involved in inflammation; 4) decreased adipose tissue ceramide content; 5) decreased plasma PAI-1 and leptin concentrations and increased plasma high-molecular weight (HMW) adiponectin; and 6) decreased plasma small extracellular vesicle (sEV) concentration and the sEV content of microRNAs proposed to inhibit insulin action, and completely reversed the inhibitory effect of plasma sEVs on insulin signaling in myotubes. CONCLUSIONS: These findings suggest that weight loss increases insulin sensitivity in people with obesity and type 2 diabetes by modifying adipose tissue biology, with concomitant alterations in circulating PAI-1, leptin, HMW adiponectin, and sEV microRNAs.

  PublisherDOI

• Response to Comment on Samovski et al. Effect of Marked Weight Loss on Adipose Tissue Biology in People With Obesity and Type 2 Diabetes. Diabetes Care 2025;48:1342–1351

  Diabetes Care · 2025-11-20

  articleOpen access
  PublisherOA PDFDOI

• Cell-intrinsic insulin signaling defects in human iPS cell–derived hepatocytes in type 2 diabetes

  Journal of Clinical Investigation · 2025-04-14 · 6 citations

  articleOpen accessSenior author

  Hepatic insulin resistance is central to type 2 diabetes (T2D) and metabolic syndrome, but defining the molecular basis of this defect in humans is challenging because of limited tissue access. Utilizing inducible pluripotent stem cells differentiated into hepatocytes from control individuals and patients with T2D and liquid chromatography with tandem mass spectrometry-based (LC-MS/MS-based) phosphoproteomics analysis, we identified a large network of cell-intrinsic alterations in signaling in T2D. Over 300 phosphosites showed impaired or reduced insulin signaling, including losses in the classical insulin-stimulated PI3K/AKT cascade and their downstream targets. In addition, we identified over 500 phosphosites of emergent, i.e., new or enhanced, signaling. These occurred on proteins involved in the Rho-GTPase pathway, RNA metabolism, vesicle trafficking, and chromatin modification. Kinome analysis indicated that the impaired phosphorylation sites represented reduced actions of AKT2/3, PKCθ, CHK2, PHKG2, and/or STK32C kinases. By contrast, the emergent phosphorylation sites were predicted to be mediated by increased action of the Rho-associated kinases 1 and 2 (ROCK1/2), mammalian STE20-like protein kinase 4 (MST4), and/or branched-chain α-ketoacid dehydrogenase kinase (BCKDK). Inhibiting ROCK1/2 activity in T2D induced pluripotent stem cell-derived hepatocytes restored some of the alterations in insulin action. Thus, insulin resistance in the liver in T2D did not simply involve a loss of canonical insulin signaling but the also appearance of new phosphorylations representing a change in the balance of multiple kinases. Together, these led to altered insulin action in the liver and identified important targets for the therapy of hepatic insulin resistance.

  PublisherDOI

• Protein Kinase C δ: a critical hub regulating macrophage immunomodulatory functions during <i>Mycobacterium tuberculosis</i> infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-23

  preprintOpen access

  Abstract A host-modulating candidate gene involved in putative pathogen-killing pathways, with potential novel therapeutic intervention, Protein Kinase C – δ (PKCδ) has been recognized as a critical marker of inflammation with clinical and experimental evidence in recent years. Pulmonary microenvironment during Mtb infection is largely governed by lung resident macrophages, initiating innate and subsequent adaptive immune responses. We investigated the role of PKCδ in macrophages using a macrophage-specific PKCδ knockout mice model (LysM cre PKCδ flox/flox ). PKCδ deficiency in macrophages triggers an early lymphocytic immune response, increases neutrophil recruitment, and reduces inflammatory macrophages in the lungs, leading to higher Mtb burden and exacerbated pathology. Experimental and omics analysis further revealed that dysregulation of antimicrobial effector functions is detrimental to macrophage’s ability to restrict bacterial growth in vitro . Importantly this defect was mitigated by exogenous GM-CSF supplementation and/or overexpressing PKCδ in macrophages. Thus, PKCδ plays a crucial role in immune modulation during Mtb infection with GM-CSF amongst several downstream pathways through which PKCδ exerts its regulatory effects. Teaser PKCδ is crucial for immune modulation during Mtb infection revealing macrophages as a potential axis of signaling.

  PublisherOA PDFDOI

• &lt;b&gt;Effect of Marked Weight Loss on Adipose Tissue Biology in People with Obesity and Type 2 Diabetes&lt;/b&gt;

  2025-04-10 · 1 citations

  preprintOpen access

  &lt;p dir="ltr"&gt;&lt;b&gt;Objective&lt;/b&gt;: Weight loss improves insulin sensitivity in people with obesity and type 2 diabetes. However, the mechanisms responsible for this effect are unclear. We hypothesized that alterations in adipose tissue biology and adipose tissue-related factors in plasma are involved in mediating the systemic metabolic benefits of weight loss.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Research Design and Methods&lt;/b&gt;: We evaluated blood and adipose tissue samples obtained from ten adults with obesity and type 2 diabetes before and after marked (16%-20%) weight loss and &gt;50% increase in whole-body insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Results: &lt;/b&gt;Weight loss: &lt;a href="" target="_blank"&gt;i) &lt;/a&gt;&lt;a href="" target="_blank"&gt;decreased adipose tissue &lt;/a&gt;expression of genes related to extracellular matrix remodeling; ii) decreased adipose tissue expression of SERPINE 1 which encodes plasminogen activator inhibitor-1 (PAI-1); iii) did not decrease adipose tissue immune cell content or expression of genes involved in inflammation; iv) decreased adipose tissue ceramide content; v) decreased plasma &lt;a href="" target="_blank"&gt;PAI-1 &lt;/a&gt;and leptin concentrations and increased plasma high-molecular weight (HMW) adiponectin; and vi) decreased plasma small extracellular vesicle (sEV) concentration and the sEV content of microRNAs proposed to inhibit insulin action, and completely reversed the inhibitory effect of plasma sEVs on insulin signaling in myotubes.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Conclusions: &lt;/b&gt;These findings suggest that weight loss increases insulin sensitivity in people with obesity and type 2 diabetes by modifying adipose tissue biology with concomitant alterations in circulating PAI-1, leptin, HMW adiponectin and sEV microRNAs.&lt;/p&gt;

  PublisherOA PDFDOI

• &lt;b&gt;Effect of Marked Weight Loss on Adipose Tissue Biology in People with Obesity and Type 2 Diabetes&lt;/b&gt;

  2025-04-10

  preprintOpen access

  &lt;p dir="ltr"&gt;&lt;b&gt;Objective&lt;/b&gt;: Weight loss improves insulin sensitivity in people with obesity and type 2 diabetes. However, the mechanisms responsible for this effect are unclear. We hypothesized that alterations in adipose tissue biology and adipose tissue-related factors in plasma are involved in mediating the systemic metabolic benefits of weight loss.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Research Design and Methods&lt;/b&gt;: We evaluated blood and adipose tissue samples obtained from ten adults with obesity and type 2 diabetes before and after marked (16%-20%) weight loss and &gt;50% increase in whole-body insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Results: &lt;/b&gt;Weight loss: &lt;a href="" target="_blank"&gt;i) &lt;/a&gt;&lt;a href="" target="_blank"&gt;decreased adipose tissue &lt;/a&gt;expression of genes related to extracellular matrix remodeling; ii) decreased adipose tissue expression of SERPINE 1 which encodes plasminogen activator inhibitor-1 (PAI-1); iii) did not decrease adipose tissue immune cell content or expression of genes involved in inflammation; iv) decreased adipose tissue ceramide content; v) decreased plasma &lt;a href="" target="_blank"&gt;PAI-1 &lt;/a&gt;and leptin concentrations and increased plasma high-molecular weight (HMW) adiponectin; and vi) decreased plasma small extracellular vesicle (sEV) concentration and the sEV content of microRNAs proposed to inhibit insulin action, and completely reversed the inhibitory effect of plasma sEVs on insulin signaling in myotubes.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Conclusions: &lt;/b&gt;These findings suggest that weight loss increases insulin sensitivity in people with obesity and type 2 diabetes by modifying adipose tissue biology with concomitant alterations in circulating PAI-1, leptin, HMW adiponectin and sEV microRNAs.&lt;/p&gt;

  PublisherDOI

• 285-OR: A Kinase-Mediated Signaling and Glucose Uptake Defect in Human Insulin Resistance

  Diabetes · 2025-06-13

  articleSenior author

  Introduction and Objective: Insulin resistance is a major risk factor in the development of type 2 diabetes (T2D) and metabolic syndrome. Although ~25% of people within the general non-diabetic population are insulin resistant, the primary underlying cause of insulin resistance remains elusive. Methods: In this study, we have used induced pluripotent stem cells (iPSC) derived from non-diabetic humans at both ends of the insulin sensitivity spectrum, i.e., the top 20% of insulin resistance vs. the top 20% of insulin sensitivity differentiated into myoblasts (iMyos) to model insulin resistance in vitro. Results: Global phosphoproteomics analysis of these cells showed a large network of protein phosphorylations linked to differences in insulin sensitivity including 378 up-regulated and 393 down-regulated insulin stimulated phosphosites in I-Res iMyos. To identify drivers of altered phosphorylation in insulin resistance, we used an in silico AI kinome analysis to query which of the 300+ Ser/Thr kinases encoded in the human genome might be responsible for the protein phosphorylation changes. We could identify 16 kinases whose predicted activities were significantly increased in I-Res iMyos, suggesting their potential link to the pathogenesis of insulin resistance. To functionally link these altered kinases to the downstream defect of impaired glucose uptake associated with insulin resistance, we conducted a loss-of-function screen using a CRISPR-based approach to identify candidate kinases, or phosphatases that regulate glucose uptake in I-Res iMyos. Among the 16 kinases predicted to have increased activity in insulin resistance, one kinase, DYRK2, was identified as a potential modulator of insulin resistance by being both increased in predicted activity in I-Res iMyos and associated with rescued glucose uptake in I-Res iMyos by CRISPR-mediated knockdown. Conclusion: In summary, combining a Kinome analysis with CRISPR screening and population genetics reveals DYRK2 as an important upstream regulator of human insulin resistance. Disclosure N. Haider: None. T. Yaron-Barir: Other Relationship; DeStroke. J.L. Johnson: None. L. Cantley: Stock/Shareholder; Larkspur, Volastra, Cell Signaling Technologies. Consultant; Manas. P. Yi: None. C. Kahn: Consultant; Novo Nordisk, Cellarity. Advisory Panel; TIXiMED. Board Member; 1825.

  PublisherDOI

• Lrtm1 - A Novel Sensor of Insulin Signaling and Regulator of Metabolism and Activity

  Diabetes · 2025-02-07

  articleOpen accessSenior author

  Insulin regulates glucose uptake and metabolism in muscle via the insulin receptor. Here, we show that Lrtm1 (leucine-rich repeat and transmembrane domain 1), a protein of unknown function enriched in insulin-responsive metabolic tissues, senses changes in insulin signaling in muscle and serves as a regulator of metabolic response. Thus, whole-body Lrtm1-deficient mice exhibit a reduced percentage of fat mass, an increased percentage of lean mass, and an enhanced glucose tolerance and insulin sensitivity compared with control mice under both chow and high-fat diet conditions. Lrtm1 whole-body deficiency also affects dopamine signaling in the brain, leading to hyperactivity. The improvements in glucose and insulin tolerance, but not behavioral or body composition changes, are also observed in skeletal muscle-specific Lrtm1 knockout mice. These effects occur with no change in classical insulin receptor-Akt signaling. Thus, Lrtm1 senses changes in insulin receptor signaling and serves as a novel postreceptor regulator of metabolic and behavioral activity.

  PublisherOA PDFDOI

• Loss of insulin signaling in microglia impairs cellular uptake of Aβ and neuroinflammatory response exacerbating AD-like neuropathology

  Proceedings of the National Academy of Sciences · 2025-05-19 · 13 citations

  articleOpen accessSenior authorCorresponding

  Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimer's disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in the brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprogramming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism and the ability of the cells to take up Aβ, such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together, these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.

  PublisherDOI

• Multi-step regulation of microRNA expression and secretion into small extracellular vesicles by insulin

  Cell Reports · 2024-07-01 · 8 citations

  articleOpen accessSenior authorCorresponding

  Tissues release microRNAs (miRNAs) in small extracellular vesicles (sEVs) including exosomes, which can regulate gene expression in distal cells, thus acting as modulators of local and systemic metabolism. Here, we show that insulin regulates miRNA secretion into sEVs from 3T3-L1 adipocytes and that this process is differentially regulated from cellular expression. Thus, of the 53 miRNAs upregulated and 66 miRNAs downregulated by insulin in 3T3-L1 sEVs, only 12 were regulated in parallel in cells. Insulin regulated this process in part by phosphorylating hnRNPA1, causing it to bind to AU-rich motifs in miRNAs, mediating their secretion into sEVs. Importantly, 43% of insulin-regulated sEV-miRNAs are implicated in obesity and insulin resistance. These include let-7 and miR-103, which we show regulate insulin signaling in AML12 hepatocytes. Together, these findings demonstrate an important layer to insulin's regulation of adipose biology and provide a mechanism of tissue crosstalk in obesity and other hyperinsulinemic states.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01DK045935

  NIH · $4.2M · 2003

• Developmental genes, miRNAs and adipose tissue

  NIH · $10.7M · 2009–2027

• The Insulin Receptor and Its Signaling Mechanisms

  NIH · $8.8M · 1982–2031

• Role of PI 3-Kinase Isoforms in Insulin Action

  NIH · $8.8M · 1999–2021

• NIH Grant R01DK060837

  NIH · $15.9M · 2009

Frequent coauthors

• Yu‐Hua Tseng

  Harvard University

  223 shared

• George L. King

  Joslin Diabetes Center

  171 shared

• Jesse Roth

  Feinstein Institute for Medical Research

  148 shared

• Weikang Cai

  New York Institute of Technology

  125 shared

• Samir Softic

  University of Kentucky

  117 shared

• Masato Kasuga

  Institute for Adult Diseases Asahi Life Foundation

  116 shared

• Rohit Kulkarni

  Harvard University

  114 shared

• Jonathon N. Winnay

  112 shared

Education

• M.D.

  Harvard Medical School

• B.S.

  University of California, Berkeley

Awards & honors

• Wolf Prize in Medicine
• Kober Medal of the AAP
• highest honors of the American Diabetes Association
• highest honors of the U.S. Endocrine Society
• highest honors of the British Endocrine Society