Insulin

Insulin

1. Mechanisms of action

   • Direct Insulin Action
     • Proximal Insulin Signaling
       • Upon insulin binding, the insulin receptor (INSR) autophosphorylates and recruits diverse substrates. The two major arms of insulin signaling are mitogenic (initiated by GRB2 and SHC) and metabolic [initiated by insulin receptor substrate (IRS) proteins and SH2B2/APS]. Insulin signaling is also characterized by feedback mechanisms, both positive [GIV potentiation of phosphoinositide-3-kinase (PI3K)-AKT signaling, and phosphatase inhibition by NAD(P)H oxidase 4 (NOX4)-derived H2O2] and negative (stabilization and recruitment of GRB10 to the INSR, and activation of S6 kinase 1 (S6K1) to phosphorylate and inhibit IRS proteins)
     • Skeletal Muscle Insulin Signaling
       • Insulin receptor (INSR) activation has two major metabolic functions in the skeletal myocyte: glucose uptake and glycogen storage. Insulin stimulation of glucose uptake occurs through translocation of GLUT4-containing storage vesicles (GSVs) to the plasma membrane. The resultant increase in intracellular glucose-6-phosphate production, together with a coordinated dephosphorylation of glycogen metabolic proteins, enables net glycogen synthesis.
     • Hepatic Insulin Signaling
       • AKT signaling is central to hepatocellular insulin action. Fast effects include activation of the glycogen and protein synthetic machinery. Slower transcriptionally mediated effects include upregulation of glucokinase, dimunition of gluconeogenic capacity, and stimulation of de novo lipogenic capacity.
     • White Adipocyte Insulin Signaling
       • The most critical physiological functions of insulin action in white adipose tissue are suppression of lipolysis and stimulation of glucose uptake. Suppression of lipolysis requires phosphodiesterase 3B (PDE3B) and occurs largely through attenuation of cAMP-stimulated events such as perilipin (PLIN) and hormone-sensitive lipase (HSL) phosphorylation. Insulin stimulation of glucose uptake occurs through phosphoinositide-3-kinase (PI3K)-dependent [left insulin receptor (INSR)] and PI3K-independent (right INSR) pathways using numerous effectors to promote translocation, docking, and fusion of GLUT-containing storage vesicles (GSVs) with the plasma membrane.
   • Indirect Insulin Action
     • Lipolytic Control of Hepatic Gluconeogenesis
       • A: in the fasted state, the adipocyte releases nonesterified fatty acids (NEFA) into the circulation. Within the hepatocyte, NEFA are oxidized to mitochondrial acetyl CoA, an allosteric activator of pyruvate carboxylase (PC). PC drives gluconeogenic flux. This, together with net glycogenolysis, facilitates hepatic glucose production (HGP) during fasting. B: during insulin stimulation (e.g., postprandially), both direct and indirect effects of insulin suppress HGP. Adipocyte insulin signaling suppresses lipolysis, decreasing plasma NEFA concentrations, hepatic mitochondrial acetyl CoA concentrations, PC activity, and gluconeogenic flux. Simultaneously, direct insulin action on the hepatocyte promotes net glycogen synthesis. Both processes enable insulin to rapidly and potently suppress net HGP.
     • . Insulin Suppression of Glucagon Secretion
       • Glucagon action is important for normal glucose homeostasis, and given its potent anti-insulin effects on the liver in particular, it is not surprising that an elegant and tightly controlled reciprocal paracrine regulatory system has evolved to favor either insulin or glucagon secretion, but not both, in any given metabolic state. Insulin per se is sufficient to suppress glucagon levels during euglycemia and hypoglycemia in humans with type 1 diabetes (T1D), and fasting glucagon levels are correlated with insulin resistance in nondiabetic humans
     • Peripheral Effects of CNS Insulin Action
       • CNS signaling has been demonstrated to regulate hepatic insulin action through mechanisms independent of energy balance. The 2002 finding that intracerebroventricular insulin administration was sufficient to suppress hepatic glucose production in rodents (after a >1 h time delay) spurred further investigation in the field. Subsequently, insulin action in certain hypothalamic nuclei was reported to potently suppress hepatic glucose production, promote muscle glucose uptake, suppress adipose tissue lipolysis, and suppress glucagon secretion in rodents.

2. Mechanisms of resistance

   • Lipid-Induced Insulin Resistance
     • The DAG-Novel Protein Kinase C Axis and Insulin Resistance
       • . Various genetic loss-of-function and gain-of function rodent models have been generated to test the role of diacylglycerol (DAG) in lipid-induced hepatic insulin resistance. These models are broadly consistent with the DAG/protein kinase C (PKC)ε hypothesis of lipid-induced hepatic insulin resistance.
     • Ceramides and Insulin Resistance
       • The role of ceramides in adipose insulin resistance is unclear, but research in this area is accelerating. Human studies have reported correlation of adipose ceramide content with HOMA-IR and increased adipose ceramides in obese diabetic compared with obese nondiabetic subjects. Additionally, the whole-body insulin sensitization associated with adipose-specific induction of ceramide degradation suggests a role for adipose ceramides in insulin action, whether direct or via tissue cross-talk.
     • Acylcarnitines, Metabolic Inflexibility, and Insulin Resistance
       • The physiological rationale for acylcarnitine-induced insulin resistance is unclear. Muscle acylcarnitine concentrations are regulated by nutritional status in insulin-sensitive rats, and HFD-induced muscle insulin resistance is accompanied by loss of this nutritional regulation but does not cause absolute increases in acylcarnitine concentrations compared with levels in fasted, chow-fed rodents
   • Cellular Nutrient Stress And Insulin Resistance
     • Endoplasmic Reticulum Stress and Insulin Resistance
       • A: endoplasmic reticulum (ER) stress, manifested as the unfolded protein response (UPR), is activated in multiple models of liver insulin resistance. Accumulation of misfolded proteins in the ER lumen initiates the UPR, activating PKR-like eukaryotic initiation factor 2α kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Key effectors of the UPR include c-Jun NH2-terminal kinase (JNK) and the mRNA splice variant of X-box binding protein 1 (XBP1s). JNK may directly impair proximal insulin signaling, although this is controversial. XBP1s transcriptionally activates the de novo lipogenic program and promotes hepatic steatosis, which may in turn drive hepatic insulin resistance through diacylglycerol (DAG)/protein kinase C (PKC)ε signaling. B: muscle insulin resistance is associated with mitochondrial dysfunction, although cause and effect relationships are not clearly defined. The red pathway describes observations made in humans: older adults
     • Mitochondrial Energetics, Oxidative Stress, and Insulin Resistance
       • There is experimental evidence for the hypothesis that blocking mitochondrial ROS production can prevent muscle insulin resistance. Scavenging mitochondrial H2O2, either through pharmacological means or by transgenically expressing catalase in mitochondria (MCAT mice), protects against HFD-induced muscle insulin resistance. Notably, the MCAT mice were also protected from age-induced muscle insulin resistance, associated with preserved mitochondrial activity and decreased DAG/PKCθ axis activation compared with aged wild-type mice
   • Integrated Physiological Mechanisms Of Insulin Resistance
     • The Macrophage-Adipocyte Interaction and Inflammatory Signaling in Insulin Resistance
       • The basic model for inflammation-induced insulin resistance is a “two-hit” model in which macrophage activation is followed by macrophage elaboration of paracrine and/or endocrine factors which induce insulin resistance in target cells such as adipocytes or hepatocytes (594). Both processes have been well studied and are complex.
     • Circulating Branched-Chain Amino Acids and Insulin Resistance
       • The interaction between plasma amino acids and glucose homeostasis is complex, with effects on insulin secretion, hepatic glucose production, and peripheral glucose disposal all well-established (72, 238, 435). Interest in the link between BCAAs and insulin resistance has been reinvigorated in the 21st century by metabolomics methods that have confirmed a strong association between the HOMA-IR score and circulating BCAA concentration
     • Adipokines and Hepatokines in Insulin Resistance
       • An intriguing link between adiponectin and other paradigms of insulin resistance was revealed in the 2011 report that activation of the adiponectin receptors AdipoR1 and AdipoR2 induces a ceramidase (i.e., ceramide-degrading) activity. Although likely not sufficient to explain the acute suppression of HGP by adiponectin, liver-specific ceramidase activation in the chronic setting is sufficient to prevent hepatosteatosis and HFD-induced hepatic insulin resistance.