Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Aug 3;19(9):77.
doi: 10.1007/s11892-019-1195-5.

Regulation of Glucose Production in the Pathogenesis of Type 2 Diabetes

Ashot Sargsyan  1 , Mark A Herman  2   3
Affiliations
Review

Regulation of Glucose Production in the Pathogenesis of Type 2 Diabetes

Ashot Sargsyan et al. Curr Diab Rep. .

Abstract

Purpose of review: Increased glucose production associated with hepatic insulin resistance contributes to the development of hyperglycemia in T2D. The molecular mechanisms accounting for increased glucose production remain controversial. Our aims were to review recent literature concerning molecular mechanisms regulating glucose production and to discuss these mechanisms in the context of physiological experiments and observations in humans and large animal models.

Recent findings: Genetic intervention studies in rodents demonstrate that insulin can control hepatic glucose production through both direct effects on the liver, and through indirect effects to inhibit adipose tissue lipolysis and limit gluconeogenic substrate delivery. However, recent experiments in canine models indicate that the direct effects of insulin on the liver are dominant over the indirect effects to regulate glucose production. Recent molecular studies have also identified insulin-independent mechanisms by which hepatocytes sense intrahepatic carbohydrate levels to regulate carbohydrate disposal. Dysregulation of hepatic carbohydrate sensing systems may participate in increased glucose production in the development of diabetes.

Keywords: ChREBP; Diabetes; Gluconeogenesis; Glucose 6 phosphate; Glucose production; Glycogenolysis.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

Ashot Sargsyan declares that he has no conflict of interest.

Figures

Figure 1.
Figure 1.
Insulin binds the Insulin receptor and activates AKT, which enhances glycogen synthesis by activating glycogen synthase (GS), and repressing glycogen phosphorylase (GP). Activated AKT also inhibits the transcription factor FOXO1 leading to decreased expression of gluconeogenic enzymes including glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (PCK1) and increased expression of glucokinase (GCK) which enhances hepatic glucose uptake. The transcription factor ChREBP senses cellular glucose-6-phosphate (G6P) levels and mediates cellular G6P homeostasis by enhancing expression of enzymes that dispose of G6P including G6PC and liver pyruvate kinase (Pklr). Enzymes labeled in red increase G6P production, whereas enzymes labeled in blue contribute to G6P disposal.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282(12):668–75. doi:10.1056/NEJM197003192821209. - DOI - PubMed
    1. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837–53. - PubMed
    1. Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care. 1979;2(2):120–6. - PubMed
    1. Ekberg K, Landau BR, Wajngot A, Chandramouli V, Efendic S, Brunengraber H et al. Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting. Diabetes. 1999;48(2):292–8. - PubMed
    1. Pagliassotti MJ, Cherrington AD. Regulation of net hepatic glucose uptake in vivo. Annu Rev Physiol. 1992;54(1):847–60. doi:10.1146/annurev.ph.54.030192.004215. - DOI - PubMed

Publication types

  NODES
twitter 2