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Metabolic Adaptations in Diabetes Mellitus and Cancer

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Exploring Pancreatic Metabolism and Malignancy

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Abstract

A web of interconnected and flexible metabolic pathways helps in maintaining cellular homeostasis. These flexible metabolic pathways are further deregulated to ensure cell survival during clinical conditions such as diabetes and cancer. In fact, complex metabolic programming is a hallmark of both diabetes and cancer. Normally, glucose absorbed by cells is catabolized through glycolysis to form pyruvate. Pyruvate fuels the citric acid cycle in the mitochondria of aerobic cells. Diabetic condition is presented with a battery of glycolytic abnormalities. Glucose-6-phosphate derived from glucose is converted back to glucose and pumped out of the cell. Similarly, pyruvate is also converted back to glucose. Import of glucose via GLUT4 is also impaired during diabetes. In spite of decelerated glycolysis, gluconeogenesis also occurs in diabetes. In diabetic settings, cells adapt to using acetyl-CoA derived from fatty acids to fuel citric acid cycle. Cancer cells also present with several metabolic abnormalities where glucose-6-phosphate powers pentose phosphate pathway and contribute ribose required for the rapid proliferation of transformed cells. Cancer cells convert pyruvate to lactate, which is transported out of cells. Glutamine provides the majority of anaplerotic carbon for the citric acid cycle, and acetyl-CoA derived from citrate contributes to the synthesis of fatty acids. Both 3-phosphoglycerate and pyruvate are spared for the synthesis of amino acids. In the case of diabetes, cells uptake very less glucose compared with normal cells, whereas in case of cancer, cells consume excess glucose due to aerobic glycolysis. In this chapter, we will discuss the major components of the metabolic deregulations in diabetes and cancer.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

ACLY:

ATP citrate lyase

ACS:

Acetyl-CoA synthetase

ACTH:

Adrenocorticotropic hormone

AGEs:

Advanced glycation end products

AKT:

Serine-threonine protein kinase

AMPK:

AMP-dependent protein kinase

BRAF:

B-Raf proto-oncogene

CCK:

Cholecystokinin

CML:

Carboxymethyl-lysine

c-Myc:

Cellular myelocytomatosis

CREBP:

cAMP-response element-binding protein

DAG:

Diacylglycerol

ETC:

Electron transport chain

FAS:

Fatty acid synthase

G6P:

Glucose-6-phosphate

G6PDH:

Glucose-6-phosphate dehydrogenase

GLP1:

Glucagon-like peptide-1

GLS1:

Glutaminase-1/L-glutaminase

GLUT4:

Glucose transporter type 4

GOLD:

Glyoxal-lysine dimer

GPAT:

Glycerol-3-phosphate acyltransferase

GSH:

Glutathione

GSSG:

Glutathione disulfide

HIF1α:

Hypoxia-inducible factor 1α

IDH:

Isocitrate dehydrogenase

IDO:

Indoleamine 2,3-dioxygenase

IGFBP3:

Insulin-like growth factor-binding protein

IKKb:

Inhibitory kB kinase b

IRS:

Insulin receptor substrate

LDHA:

Lactate dehydrogenase A

MOLD:

Methylglyoxal-lysine dimer

mTORC:

Mammalian target of rapamycin complex 1

NF-kB:

Nuclear factor-kB

α-KG:

α-ketoglutarate

PC:

Pyruvate carboxylase

PDH:

Pyruvate dehydrogenase

PEPCK:

Phosphoenolpyruvate carboxykinase

PFK:

Phosphofructokinase

PHGDH:

Phosphoglycerate dehydrogenase

PTEN:

Phosphatase and tensin homolog

SCD:

Stearoyl-CoA desaturase

SHMT1:

Serine hydroxymethyltransferase

SREBP1:

Sterol response element-binding protein

T1D and T2D:

Type 1 diabetes and type 2 diabetes

TDO:

Tryptophan 2,3-dioxygenase

TIGAR:

TP53-induced glycolysis and apoptosis regulator

TPH1:

Tryptophan hydroxylase 1

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Acknowledgments

Authors thank Rajkishor Nishad, Lakshmi Prasanna, and Deepti Nabariya for their assistance during the preparation of this chapter.

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Authors and Affiliations

  1. Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India

    Anil Kumar Pasupulati

  2. Cancer Genomics Lab, Department of Biotechnology, SASTRA Deemed University, Thanjavur, India

    Nageswara Rao Dunna

  3. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Srikanth Talluri

Authors
  1. Anil Kumar Pasupulati
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  2. Nageswara Rao Dunna
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  3. Srikanth Talluri
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Corresponding author

Correspondence to Anil Kumar Pasupulati .

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Editors and Affiliations

  1. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    Ganji Purnachandra Nagaraju

  2. Department of Animal Biology, University of Hyderabad, Hyderabad, Telangana, India

    Aramati BM Reddy

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Pasupulati, A.K., Dunna, N.R., Talluri, S. (2019). Metabolic Adaptations in Diabetes Mellitus and Cancer. In: Nagaraju, G., BM Reddy, A. (eds) Exploring Pancreatic Metabolism and Malignancy. Springer, Singapore. https://doi.org/10.1007/978-981-32-9393-9_4

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