Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes

Chung, Stephanie T.; Hsia, Daniel S.; Chacko, Shaji; Rodríguez, Luisa M.; Haymond, Morey W.

doi:10.1007/s00125-014-3455-x

Cited by 51 publications

(43 citation statements)

References 54 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, elevated hepatic gluconeogenesis is also a hallmark of type 2 diabetes and a primary contributing factor to fasting hyperglycemia (2). A better understanding of cross-talk among the various signaling pathways that regulate hepatic gluconeogenesis during normal fasting and refeeding cycles and in type 2 diabetes will aid the design of rational therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

“…Hepatic gluconeogenesis is a critical mechanism for endogenous glucose production during periods of prolonged fasting. However, deregulated hepatic gluconeogenesis is a common feature in patients with type 2 diabetes (T2D) 2 (2). Expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatases (G6Pase) (3), key rate-limiting enzymes for hepatic gluconeogenesis, increases abnormally in T2D (4).…”

mentioning

confidence: 99%

See 1 more Smart Citation

TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis

Yadav

Devalaraja

Chung

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Edited by Jeffrey E. PessinMaintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-␤1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-␤1/Smad3 signals suppressed endogenous glucose production. TGF-␤1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-␤1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-␤1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.Glucose homeostasis is achieved via the integration of physiological processes occurring in multiple organs. Glycolysis and gluconeogenesis represent two competing processes that regulate blood glucose levels (1). Hepatic gluconeogenesis is a critical mechanism for endogenous glucose production during periods of prolonged fasting. However, deregulated hepatic gluconeogenesis is a common feature in patients with type 2 diabetes (T2D) 2 (2). Expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatases (G6Pase) (3), key rate-limiting enzymes for hepatic gluconeogenesis, increases abnormally in T2D (4). Likewise, the transgenic overexpression of these enzymes in mice results in hyperglycemia, hyperinsulinemia, and insulin resistance (5, 6). In contrast, deletion of PEPCK reverses hyperglycemia and insulin resistance in diabetes-prone db/db mice (7).The AMP-activated protein kinase (AMPK) signaling pathway, among others, regulates the expression of PEPCK and G6Pase (8). AMPK is a heterotrimeric protein, consisting of ␣1/2, ␤1/2, and ␥1/2/3 subunits, that regulates glucose and fatty acid metabolism (9). Phosphorylation of Thr-172 in the ␣1 subunit is important for AMPK activation, which is in turn regulated by two upstream kinases, LKB1 and Ca 2ϩ calmodulin-dependent protein kinases ␣ ...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis

Yadav

Devalaraja

Chung

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Subjects continued their preadmission medications throughout the study, including oral hypoglycemic agents, lipid-lowering medications, and other medications either related or unrelated to lipodystrophy and its complications. Subjects with newly diagnosed type 2 diabetes and obese adolescent subjects without diabetes were enrolled in a study during 2012 at Texas Children's Hospital (25). Type 2 diabetes was diagnosed based on American Diabetes Association criteria (26).…”

Section: Methodsmentioning

confidence: 99%

Free fatty acid processing diverges in human pathologic insulin resistance conditions

Sekizkardes

Chung

Chacko

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

BACKGROUND. Postreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptorlevel IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis. METHODS.Cross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured. RESULTS.Lipolysis was 2-to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). β-hydroxybutyrate was 2-to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation. CONCLUSION.These data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897. FUNDING.

show abstract

“…In humans, insulin resistance in obese adolescents initially involves an increase in hepatic gluconeogenesis (7) that progresses (8). Similarly, in mouse diet-induced obesity (DIO), caloric excesses provoke initial increases in hepatic gluconeogenic enzymes that lead to systemic insulin resistance and liverdependent decreases in insulin signaling in muscle (3, 4).…”

Section: Introductionmentioning

confidence: 99%

BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1α in livers of obese and type 2 diabetic humans

2015

View full text Add to dashboard Cite

Information on insulin resistance in human liver is limited. In mouse diet-induced obesity (DIO), hepatic insulin resistance initially involves: lipid + insulin-induced activation of atypical protein kinase C (aPKC); elevated Akt activity/activation but selective impairment of compartmentalized Akt-dependent FoxO1 phosphorylation; and increases in gluconeogenic and lipogenic enzymes. In advanced stages, e.g., in hepatocytes of type 2 diabetes (T2D) humans, insulin activation of insulin receptor substrate-1(IRS-1) and Akt fails, further increasing FoxO1-dependent gluconeogenic/lipogenic enzyme expression. Increases in hepatic PGC-1α also figure prominently, but uncertainly, in this scheme. Here, we examined signaling factors in liver samples harvested from human transplant donors with increasing BMI, 20→25→30→35→40→45. We found, relative to lean (BMI=20–25) humans, obese (BMI>30) humans had all abnormalities seen in early mouse DIO, but, surprisingly, at all elevated BMI levels, had decreased insulin receptor-1 (IRS-1) levels, decreased Akt activity, and increased expression/abundance of aPKC-ι and PGC-1α. Moreover, with increasing BMI, there were: progressive increases in aPKC activity and PKC-ι expression/abundance; progressive decreases in IRS-1 levels, Akt activity and FoxO1 phosphorylation; progressive increases in expression/abundance of PGC-1α; and progressive increases in gluconeogenic and lipogenic enzymes. Remarkably, all abnormalities reached T2D levels at higher BMI levels. Most importantly, both “early” and advanced abnormalities were largely reversed by 24-hour treatment of T2D hepatocytes with aPKC inhibitor. We conclude: hepatic insulin resistance in human obesity is: advanced; BMI-correlated; and sequentially involves increased aPKC-activating ceramide; increased aPKC levels and activity; decreases in IRS-1 levels, Akt activity, and FoxO1 phosphorylation; and increases in expression/abundance of PGC-1α and gluconeogenic and lipogenic genes.

show abstract

Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes

Cited by 51 publications

References 54 publications

TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis

TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis

Free fatty acid processing diverges in human pathologic insulin resistance conditions

BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1α in livers of obese and type 2 diabetic humans

Contact Info

Product

Resources

About