Resolving the Paradox of Hepatic Insulin Resistance

“016 Mdiabetes mellitus (T2DM) have reached epidemic proportions and continue to be a leading cause of death worldwide.(1) The liver plays a central role in the systemic regulation of glucose and lipid metabolism and aberrant hepatic insulin action is thought to be a primary driver of insulin resistance, in which highe…”

“Sterol regulatory element binding protein 1c (SREBP1c) is a member of the SREBP class of transcription factors that are key players in controlling cellular expression of genes required for lipid and cholesterol metabolism.(39) Insulin regulates SREBP1c by both enhancing its gene expression and post-translational proce…”

“SREBP proteins from the endoplasmic reticulum to the Golgi where it is cleaved, releasing the active part of SREBP to the nucleus where it regulates transcription.(44) SCAP is required for activation of all isoforms of SREBP and its deletion significantly reduces cholesterol and fatty acid synthesis in the liver.”

“3-phosphate kinase (PI3K)/Akt pathway is the key signaling pathway that mediates the effects of insulin on anabolic metabolism in all organisms.(17) When insulin binds to the insulin receptor (IR), it recruits and activates PI3K through insulin-receptor substrates (IRS), generating phosphatidylinositol (3,4,5)-trispho…”

“Patients with NAFLD almost universally show hyperinsulinemia.(6) In addition, both obese and diabetic human beings show a higher prevalence of NAFLD than lean ones.”

“regulation becausemice with germline deletion of Akt2 show insulin resistance and a diabetes-like phenotype.(28,29) Mice lacking hepatic Akt2, the most abundant hepatic isoform, have decreased lipid accumulation, and decreased de novo lipogenesis in the liver of ob/ob mice or mice subjected to a high-fat diet.”

“For example, LIRKO mice are typically smaller than wild-type mice, possibly because of defects in the insulin-like growth factor axis, and eventually the observed effects, such as hyperglycemia, disappear as a result of liver failure.(14) In these instances, inducible genetic knockouts hold some benefit because one ca…”

“Isotope labeling experiments in subjects with NAFLD showed that subjects with increased hepatic steatosis had 2fold higher rates of de novo lipogenesis and increased plasma levels of free fatty acids (FFAs) and insulin.(8) In addition to increased lipid synthesis, insulin-resistant individuals have increased rates of…”

“Glucagon is the principal counter-regulatory hormone that stimulates glycogenolysis and gluconeogenesis during fasting and opposes the hepatic actions of insulin.(84) Glucagon increases HGP by acutely stimulating glycogenolysis and chronically promoting gluconeogenesis(3,85,86) (Figure 2).”

“In pathologic states, such as obesity and T2DM, insulin fails to appropriately regulate hepatic metabolism, leading to excess production of glucose despite accelerated rates of lipid synthesis, a condition now commonly referred to as selective hepatic insulin resistance.(4) As a consequence, insulin-resistant disorder…”

“IRS proteins link the PI3K pathway to the insulin receptor by binding to phosphotyrosine residues on the insulin receptor.(18) Knockout of multiple insulin-receptor substrates prevents activation of the pathway in response to insulin, leading to insulin resistance and hyperglycemia, but not hepatic steatosis.”

“resistance.(47) However, ChREBP deficiency in obese mice also results in decreased lipid accumulation and improved insulin sensitivity.”

“However, other work has shown that insulin’s direct action on the liver dominates.32,72 Differences in experimental clamp conditions could underlie these contrasting results on the role of FFAs in the control of HGP.”

“regulation becausemice with germline deletion of Akt2 show insulin resistance and a diabetes-like phenotype.(28,29) Mice lacking hepatic Akt2, the most abundant hepatic isoform, have decreased lipid accumulation, and decreased de novo lipogenesis in the liver of ob/ob mice or mice subjected to a high-fat diet.”

“Recent genetic studies from several groups have supported these classic physiology studies and assert that FFA action on the liver drives HGP in insulin-resistant livers or livers completely devoid of hepatic insulin signaling.(32,72,95) Perry et al(95) proposed that insulin’s indirect action on the liver negates the…”

“Consistent with increased lipogenesis in insulin-resistant models, several models for diabetes in mice, such as ob/ob, involve heightened levels of SREBP1c activity.(42,43) SREBP cleavage-activating protein (SCAP) is a major regulator of SREBP activity because it chaperones”

“In vivo deletion of PTEN results in substantial lipid accumulation in the liver.(25) Studies have shown that deletion of Akt2 is sufficient to prevent lipid accumulation in livers with PTEN also removed,(26) suggesting that Akt serves as the essential downstream signaling kinase.”

“rons results in a failure of insulin to inhibit HGP but had no impact on insulin’s effects on body weight.(79) In response to insulin, activation of potassium adenosine triphosphate channels in the hypothalamus signals through the vagus nerve to the liver, which inhibit hepatic gluconeogenesis.”

“Indeed, there is a significant correlation between rates of gluconeogenesis and the extent of liver fat in NAFLD patients.(10) Therefore, during the progression of insulin resistance, insulin fails to suppress HGP yet continues to drive excess lipid synthesis, leading to the sequela of NAFLD, hyperglycemia, and hypert…”

“In addition, both obese and diabetic human beings show a higher prevalence of NAFLD than lean ones.(7) Isotope labeling experiments in subjects with NAFLD showed that subjects with increased hepatic steatosis had 2fold higher rates of de novo lipogenesis and increased plasma levels of free fatty acids (FFAs) and insul…”

“Hepatic deletion of FoxO1 in mice results in significant decreases in glycogenolysis and gluconeogenesis.(75) Surprisingly, deletion of FoxO1 in IR, IRS, and Akt knockout mice is sufficient to restore insulin’s suppressive effects on HGP in vivo despite a lack of autonomous insulin action.”

“Surprisingly, deletion of FoxO1 in IR, IRS, and Akt knockout mice is sufficient to restore insulin’s suppressive effects on HGP in vivo despite a lack of autonomous insulin action.(16,19,31,32,60,76) These data provide genetic evidence that supports classic physiological studies by Cherrington and Bergman that extrahe…”

“Surprisingly, deletion of FoxO1 in IR, IRS, and Akt knockout mice is sufficient to restore insulin’s suppressive effects on HGP in vivo despite a lack of autonomous insulin action.(16,19,31,32,60,76) These data provide genetic evidence that supports classic physiological studies by Cherrington and Bergman that extrahe…”

“Surprisingly, deletion of FoxO1 in IR, IRS, and Akt knockout mice is sufficient to restore insulin’s suppressive effects on HGP in vivo despite a lack of autonomous insulin action.(16,19,31,32,60,76) These data provide genetic evidence that supports classic physiological studies by Cherrington and Bergman that extrahe…”

“However, denervation of the hepatic branch of the vagus nerve fails to prevent insulin’s ability to suppress HGP in mice during a peripheral infusion of insulin under euglycemic clamp conditions.(83) In addition, mice”

“by regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Figure 1), and its inhibition improves glycemia in insulin-resistant and diabetic mice.(3,32,74) Hepatic deletion of FoxO1 in mice results in significant decreases in glycogenolysis and gluconeogenesis.”

“cient to increase fatty liver progression because overexpression of hepatic ChREBP in mice results in steatosis.(49) Consistent with these mouse studies, obese human beings typically have higher ChREBP expression in the liver, which correlates with fatty liver.”

“The central nervous system plays an integral role in glucose and lipid homeostasis.(77) Nutrients, metabolites, and hormones signal in various regions of the hypothalamus to control metabolism.”

“closely linked to nonalcoholic fatty liver disease (NAFLD), a disorder that can lead to liver dysfunction and progress to deadly nonalcoholic steatohepatitis.(5) Increased rates of glucose production and lipogenesis are well documented in insulin-resistant human beings.”

“The clinical findings corroborate the concept that the liver is the key driver of insulin’s wholebody action on glucose and lipid homeostasis.(13) Further supporting this statement, fat-specific deletion of the insulin receptor results in lipodystrophy along with insulin resistance and hyperglycemia.”

“Enhanced secretion of VLDL-TAG is another hallmark of people with insulin-resistant conditions, such as obesity or NAFLD.53,54 In particular, a failure of insulin to facilitate degradation of apolipoprotein B, a major protein in VLDL synthesis, as well as increased levels of FFAs and increased lipogenesis in insulin-r…”

“In addition, eliminating SCAP specifically in hepatocytes reduces lipid accumulation in the liver and is sufficient to prevent hepatic steatosis in ob/ob mice and sucrose-fed hamsters.(43) Therefore, SREBP1c is a necessary factor in lipogenic gene expression and in the development of fatty liver.”

“Genetic evidence also supports this correlation, indicating that deletion of the insulin receptor from a cells in mouse pancreas leads to enhanced glucagon secretion, leading to mild glucose intolerance, hyperglycemia, and hyperglucagonemia.(89) Because of hyperglucagonemia’s long association with diabetes, many comme…”

“For example, SREBP1c processing in transgenic rats requires S6K1, a target of mTORC1.(41) Consistent with increased lipogenesis in insulin-resistant models, several models for diabetes in mice, such as ob/ob, involve heightened levels of SREBP1c activity.”

“SCAP is required for activation of all isoforms of SREBP and its deletion significantly reduces cholesterol and fatty acid synthesis in the liver.(45) In addition, eliminating SCAP specifically in hepatocytes reduces lipid accumulation in the liver and is sufficient to prevent hepatic steatosis in ob/ob mice and sucro…”

“by regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Figure 1), and its inhibition improves glycemia in insulin-resistant and diabetic mice.(3,32,74) Hepatic deletion of FoxO1 in mice results in significant decreases in glycogenolysis and gluconeogenesis.”

“During a normal physiologic fasting period, a high glucagonto-insulin ratio decreases the rate of glucose consumption and shifts the liver to glucose production, first by consuming its stores of glycogen (glycogenolysis) and then from glucogenic precursors in a synthetic pathway (gluconeogenesis).(2) In the postprandi…”

“Mice lacking hepatic Akt2, the most abundant hepatic isoform, have decreased lipid accumulation, and decreased de novo lipogenesis in the liver of ob/ob mice or mice subjected to a high-fat diet.(30) However, despite its abundance, liver-specific deletion of Akt2 only results in mild insulin resistance owing to residu…”

“Insulin can act on neurons in the hypothalamus, particularly agouti-related peptide– and proopiomelanocortin-expressing neurons.(78) Knockout of the insulin receptor in agouti-related peptide–expressing neu-”

“Moreover, overexpressing ChREBP was not sufficient to regain any significant lipogenic gene induction in mice lacking SREBP after SCAP deletion, showing that SREBP is required for the induction of lipogenic expression.(52) The interplay between ChREBP and SREBP1c in regulating lipogenic gene expression helps ensure th…”

“by regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Figure 1), and its inhibition improves glycemia in insulin-resistant and diabetic mice.(3,32,74) Hepatic deletion of FoxO1 in mice results in significant decreases in glycogenolysis and gluconeogenesis.”

“In addition, LIRKO mice fail to accumulate lipids and do not develop fatty liver, even when fed a high-fat diet, despite increased blood glucose and insulin levels.(12) These”

“However, other work has shown that insulin’s direct action on the liver dominates.32,72 Differences in experimental clamp conditions could underlie these contrasting results on the role of FFAs in the control of HGP.”

“Conversely, deletion of all FoxO isoforms from the liver activates lipogenic gene expression and induces de novo lipogenesis correlating with hepatic steatosis.(62) Because FoxO1 is thought to be a transcriptional activator, the specific mechanisms governing its inhibition of lipogenesis is unclear.”

“These mice also fail to promote hepatic lipogenesis in response to a high carbohydrate meal.(16) Resolving what specific factors mediate insulin action on the liver to generate these paradoxical effects has become a major focus in obesity and T2DM studies and has provided many insights into the molecular mechanisms of…”

“However, recent studies have argued that FoxO1 directly represses the transcription of SREBP1c.63 In addition, FoxO1 has been implicated in regulating the expression of glucokinase (Gck) through a repression mechanism mediated by Sin3a and Sin3b62,64,65 (Figure 1).”

“Knockout of multiple insulin-receptor substrates prevents activation of the pathway in response to insulin, leading to insulin resistance and hyperglycemia, but not hepatic steatosis.(19,20) PIP3 initiates recruitment of Akt (named as such when it was discovered to be the oncogene responsible for thymoma in Ak mice, a…”

“Studies have shown that activation of mTORC1 is required for de novo lipogenesis, however, activation of mTORC1 alone is not sufficient to induce lipogenesis in the absence of hepatic insulin signaling.(32,37) This is consistent with the phenotype of mice lacking Tsc specifically in hepatocytes because liver-specific…”

“Further supporting this statement, fat-specific deletion of the insulin receptor results in lipodystrophy along with insulin resistance and hyperglycemia.(15) However, these mice are not protected from NAFLD, and eventually develop nonalcoholic steatohepatitis, unlike the LIRKO mice and human beings with insulin-recep…”

“In addition, disrupting insulin signaling in mouse livers by deleting Akt or the insulin receptor reduces VLDL secretion.(57) Downstream of Akt, inhibiting or activating mTORC1 in the liver leads to decreased or increased VLDL secretion, respectively, through the regulation of phosphatidylcholine synthesis, a crucial…”

“Downstream of Akt, inhibiting or activating mTORC1 in the liver leads to decreased or increased VLDL secretion, respectively, through the regulation of phosphatidylcholine synthesis, a crucial part of VLDL synthesis and secretion.(58) As such, insulin regulation of VLDL-TAG secretion is complex and the coordinated con…”

“due to its three active serine residues being mutated to alanines, FoxoAAA, fail to initiate transcription of lipogenic genes after feeding, leading to a reduction in lipogenesis and triglyceride secretion.(60,61) Conversely, deletion of all FoxO isoforms from the liver activates lipogenic gene expression and induces…”

“Increased gluconeogenic flux largely contributes to this effect on HGP.(94) Recent genetic studies from several groups have supported these classic physiology studies and assert that FFA action on the liver drives HGP in insulin-resistant livers or livers completely devoid of hepatic insulin signaling.”

“Recently, studies deleting ChREBP specifically in mouse hepatocytes showed mild insulin resistance and protection from hepatic steatosis when challenged with a high-carbohydrate diet, but had no effect on lipogenesis and lipogenic gene expression under normal chow.(51) Hepatic deletion of ChREBP in mice following a hi…”

“Consistent with these mouse studies, obese human beings typically have higher ChREBP expression in the liver, which correlates with fatty liver.(50) Recently, studies deleting ChREBP specifically in mouse hepatocytes showed mild insulin resistance and protection from hepatic steatosis when challenged with a high-carbo…”

“Under euglycemic clamp conditions, increased insulin concentrations led to a reduction in glucagon secretion.(87) Moreover, human studies have indicated a close correlation of insulin action and decreased glucagon concentrations, implying some effect of insulin on glucagon secretion.”

“Because of hyperglucagonemia’s long association with diabetes, many commercial antidiabetic drugs target some part of the glucagon signaling mechanism with some success.(90) Despite this well-established effect on”

“Enhanced secretion of VLDL-TAG is another hallmark of people with insulin-resistant conditions, such as obesity or NAFLD.53,54 In particular, a failure of insulin to facilitate degradation of apolipoprotein B, a major protein in VLDL synthesis, as well as increased levels of FFAs and increased lipogenesis in insulin-r…”

“Moreover, human studies have indicated a close correlation of insulin action and decreased glucagon concentrations, implying some effect of insulin on glucagon secretion.(88) Genetic evidence also supports this correlation, indicating that deletion of the insulin receptor from a cells in mouse pancreas leads to enhanc…”

“However, insulin-resistant individuals do not respond to this signaling process, and paradoxically show an increase in both hepatic glucose production and insulin secretion, which can induce or aggravate hyperglycemia.(15) The factors that promote the emergence of insulin resistance include altered insulin signaling,…”

“In humans, high pre-training levels of SeP were predictive of decreased aerobic exercise capacity, measured as VO2 max [50], suggesting that FFAs released by VAT lipolysis during and after exercise are less efficiently utilized by SkM and are instead preferentially reincorporated into VAT via VLDL.”

“In mammals, the accumulation of lipid in tissues, such as muscle and liver, is closely related to insulin resistance that associates with a myriad of metabolic disorders (84, 85).”