C. Ronald Kahn

About 25% of people in the general population are insulin resistant, increasing the risk for type 2 diabetes (T2D) and metabolic disease. Transcriptomic analysis of induced pluripotent stem cells differentiated into myoblasts (iMyos) from insulin-resistant (I-Res) versus insulin-sensitive (I-Sen) nondiabetic individuals revealed that 306 genes increased and 271 genes decreased in expression in iMyos from I-Res donors with differences of 2-fold or more. Over 30 of the genes changed in I-Res iMyos were associated with T2D by SNPs and were functionally linked to insulin action and control of metabolism. Interestingly, we also identified more than 1,500 differences in gene expression that were dependent on the sex of the cell donor, some of which modified the insulin resistance effects. Many of these sex differences were associated with increased DNA methylation in cells from female donors and were reversed by 5 …

1. Tai YT, Podar K, Catley L, Tseng YH, Akiyama M, Shringarpure R, et al. Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of b1-integrin and phosphatidylinositol 3’-kinase/AKT signaling. Cancer Res 2003; 63: 5850–58.

Pain is the prime symptom of osteoarthritis (OA) that directly affects the quality of life. Protein kinase Cδ (PKCδ/Prkcd) plays a critical role in OA pathogenesis; however, its significance in OA-related pain is not entirely understood. The present study investigated the functional role of PKCδ in OA pain sensation. OA was surgically induced in control (Prkcdfl/fl), global- (Prkcdfl/fl; ROSACreERT2), and sensory neuron-specific conditional knockout (cKO) mice (Prkcdfl/fl; NaV1.8/Scn10aCreERT2) followed by comprehensive analysis of longitudinal behavioral pain, histopathology and immunofluorescence studies. Global Prkcd cKO mice prevented cartilage deterioration by inhibiting matrix metalloproteinase-13 (MMP13) in joint tissues but significantly increased OA pain. Sensory neuron-specific deletion of Prkcd in mice did not protect cartilage from degeneration but worsened OA-associated pain. Exacerbated pain …

Insulin acts through the insulin receptor (IR) tyrosine kinase to exert its classical metabolic and mitogenic actions. Here, using receptors with either short or long deletion of the β-subunit or mutation of the kinase active site (K1030R), we have uncovered a second, previously unrecognized IR signaling pathway that is intracellular domain-dependent, but ligand and tyrosine kinase-independent (LYK-I). These LYK-I actions of the IR are linked to changes in phosphorylation of a network of proteins involved in the regulation of extracellular matrix organization, cell cycle, ATM signaling and cellular senescence; and result in upregulation of expression of multiple extracellular matrix-related genes and proteins, down-regulation of immune/interferon-related genes and proteins, and increased sensitivity to apoptosis. Thus, in addition to classical ligand and tyrosine kinase-dependent (LYK-D) signaling, the IR regulates a …

GUOXIAO WANG, YINGYING YU, WENQIANG CHEN, WEIKANG CAI, XIANGYU LIU, C. RONALD KAHN; 190-OR: Lrtm1, a Novel Regulator of Insulin Signaling and Metabolism. Diabetes 20 June 2023; 72 (Supplement_1): 190–OR. https://doi. org/10.2337/db23-190-OR

Diets high in sugar and fat promote the development of obesity and metabolic complications, while high-sugar, low-fat or high-fat, sugar-free (ketogenic) diets do not. We assessed the importance of sugar in a commonly used 60% high-fat diet (HFD), which contains 6.7% of calories from sucrose. The sucrose content was replaced either with an equal amount of fructose (HFD+ RF) or glucose (HFD+ RG) and all other components of the diet were identical. After 12 weeks on the diets, the mice on HFD and HFD+ RF diets gained more weight, developed hepatic steatosis, glucose intolerance and insulin resistance, compared to the mice on normal chow or HFD+ RG diets. A relatively small (6.7%) amount of sucrose or fructose, but not glucose, in a HFD was sufficient to increase the fructolysis (KHK-C, ALDO B and TKFC) and de novo lipogenesis (ME1, ACLY, ACC1, FASN, SCD1) pathways by WB. Metabolomics …

Over 65 % of people with obesity display the metabolic-associated fatty liver disease (MAFLD), which can manifest as steatohepatitis, fibrosis, cirrhosis, or liver cancer. The development and progression of MAFLD involve hepatic insulin resistance and reduced insulin clearance. This review discusses the relationships between altered insulin signaling, hepatic insulin resistance, and reduced insulin clearance in the development of MAFLD and how this provides the impetus for exploring the use of insulin sensitizers to curb this disease. The review also explores the role of the insulin receptor in hepatocytes and hepatic stellate cells and how it signals in metabolic and end-stage liver diseases. Finally, we discuss new research findings that indicate that advanced hepatic diseases may be an insulin-sensitive state in the liver and deliberate whether insulin sensitizers should be used to manage late-stage liver diseases.

Secondary lymphedema occurs in up to 20% of patients after lymphadenectomy performed for the surgical management of tumors involving the breast, prostate, uterus, and skin. Patients develop progressive edema of the affected extremity due to retention of protein-rich lymphatic fluid. Despite compression therapy, patients progress to chronic lymphedema in which noncompressible fibrosis and adipose tissue are deposited within the extremity. The presence of fibrosis led to our hypothesis that rosiglitazone, a PPARγ agonist that inhibits fibrosis, would reduce fibrosis in a mouse model of secondary lymphedema after hind limb lymphadenectomy. In vivo, rosiglitazone reduced fibrosis in the hind limb after lymphadenectomy. Our findings verified that rosiglitazone reestablished the adipogenic features of TGF-β1–treated mesenchymal cells in vitro. Despite this, rosiglitazone led to a reduction in adipose tissue …