The Need to Understand Glucose Metabolism in Normal and Aberrant Tissues for Diagnostic Considerations

A key hallmark of many cancers, at least the most aggressive ones, is the capacity to metabolize glucose at an elevated rate - a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells that are invasive or participate in metastasis formation a distinct competitive edge over normal cells. Adaptation to hypoxia and acidosis of tumor cells causes an upregulation of glucose transporter 1 and 3 (GLUT-1 and GLUT-3), which gives the cells an...

The Metabolic Syndrome Diabetes and Steatosis and Incidence of Hepatocellular Carcinoma

The incidence of hepatocellular carcinoma (HCC) is increasing, but the temporal changes of risk factors remain unclear. A significant proportion of HCC develops in crypto-genic cirrhosis, and may present the most worrisome complication of non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis is tightly linked to insulin resistance and several features of the MeS, e.g. obesity, diabetes and dyslipidemia. A systemic review and meta-analysis of a total of 26 studies revealed that diabetes...

Magnesium

Magnesium plays a critical role in carbohydrate metabolism and preventing metabolic syndrome. It may influence the release and activity of insulin and help balance glucose levels. Low magnesium levels are associated with the development of metabolic syndrome and type 2 diabetes. Hypomagnesemia may worsen insulin resistance, a condition that often precedes type 2 diabetes, or may be a consequence of insulin resistance. In older adults, correcting magnesium depletion may improve insulin response...

Hyperinsulinemia and Insulin Resistance Linked to Colorectal Cancer

Non-insulin-dependent diabetes mellitus (NIDDM) seems to be one risk factor for colorectal cancer. Usually, in the pre-NIDDM state, hyperinsulinemia is seen for several years. Insulin is a growth factor of epithelial and cancer cells of colon and rectum. At the Department of General Surgical Science, Gumma University, Gumma, Japan 46 , patients suffering from colorectal cancer but never diagnosed for diabetes, were tested for glucose tolerance. Serum glucose and insulin levels were found to be...

Treatment for Diabetes Mellitus A Potential Therapy for Breast Cancer

Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Some of the beneficial effects of metformin have been linked to activation of AMPK in muscle, adipose tissue, and liver. AMPK is a protein kinase which regulates energy metabolism and is activated by an increase in the intracellular ratio of AMP ATP. Upon activation, AMPK phosphorylates a number of effector proteins leading to the activation of ATP-generating pathways, such as glycolysis, and the...

Diseases Caused by Mutations of Glucose Transporters

Some diseases are described that are associated with loss-of-function mutations of glucose transporters. In addition, genome-wide scans identified SNPs in glucose transporter genes associated with a disease or altered serum parameter. SGLT1 deficiency results in the development of glucose-galactose malabsorption GMM through the intestinal brush border, an autosomal-recessive disease characterized by neonatal onset of severe watery and acidic diarrhea, which is fatal within a few weeks unless...

Dietary Modifications

Alterations in neuroendocrine-immune balance and movement toward intracellular fermentative metabolism create intracellular acidity and heightened risk for other chronic disease, including cancer. Dietary changes can reduce the progression to these shifts and are imperative in controlling inflammatory signaling and its complex milieu of comorbid symptoms, conditions, and pathologies. The focus of treating a patient with type 2 diabetes, obesity, cancer, or any other condition should be on the...

Regulation of GLUT Expression in Cancer

Some regions in tumors have low oxygenation due to poor perfusion 58 and GLUT1 expression has been shown to be upregulated in hypoxic regions surrounding necrotic foci of breast tumors and colorectal cancer 22 . Hypoxic tumors are significantly more malignant, metastatic, radio- and chemoresistant and have a poor prognosis. Hypoxia, induced in vitro, has been shown to activate uptake of FDG and to increase GLUT1 protein levels 59 . The discovery of the oxygen-sensitive transcription factor...

Abstract

Glucose, the major substrate for energy production in mammalian cells, is transported into the cell via facilitative glucose transporters GLUT . The GLUT family consists of 14 members, which differ in their tissue distribution and substrate specificity. Expression of several GLUTs is controlled by hormones and environmental factors and differential expression is involved in various disease states such as diabetes and cancer. Insulin-stimulated glucose uptake in skeletal muscle and adipose...

The Family of Glucose Transport Facilitators

Glucose transport facilitators GLUT proteins are uniporters which catalyze the diffusion of glucose into or out of cells along the concentration gradient 2, 5 . Within most cells, glucose is rapidly phosphorylated and metabolized. Thus, under normal conditions the influx of glucose into cells does not alter its concentration gradient. In liver, kidney, and intestinal mucosa, GLUT proteins catalyze the efflux of glucose from cells, when the intracellular glucose concentration exceeds the serum...

Role of Glucose Transporters for the Development of Cancer

Cancer cells require a steady source of metabolic energy in order to continue their uncontrolled growth and proliferation. Accelerated glycolysis is one of the biochemical characteristics of cancer cells. Recent work indicates that glucose transport and metabolism are essential for the post-treatment survival of tumor cells, leading to poor prognosis 46 . Glycolytic breakdown of glucose is preceded by the transport of glucose across the cell membrane, a rate-limiting process mediated by...

Metabolic Syndrome and Risk of Prostate Cancer

Currently, there is a debate whether MeS predicts the incidence of prostate cancer. The hypothesis was tested using the 27-year follow-up of the prospective cohort of the Oslo Study in 1972-1973. MeS was found to predict prostate cancer during 27 years of follow-up, indicating an association between insulin resistance and the incidence of prostate cancer 33 . Features of the MeS, specifically abdominal obesity and hypertension, are also associated with prostate cancer in African-American men 34...

Evolutionary Consequences of Hypoxia and Acidosis

Recognition of the reliable development of hypoxia in premalignant lesions has allowed the Warburg effect to be derived from modeling of cancer populations in terms of Darwinian selection 21, 25 . It is proposed that aerobic glycolysis arises through two evolutionary steps and represents a critical development in the transition from in situ to invasive cancer. The first evolutionary step is adoption of upregulated glycolysis as a result of fixed or cyclical hypoxia. This transition is observed...

W Essential Fatty Acids

W-3 fatty acids are a group of polyunsaturated fatty acids including a-linolenic acid, eicosapentaenoic acid EPA , and docosahexaenoic acid DHA that come from food sources or dietary supplements. Food sources include fish and fish oils including salmon, rainbow trout, mackerel, krill, anchovy, and sardines , flaxseed oil, berries such as lingonberry and black raspberry , walnuts, and wheat germ. However, w-3 sources that are not from fish require conversion in the body and are therefore not a...

References

1 DeBeardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB The biology of cancer metabolic reprogramming fuels cell growth and proliferation. Cell Metab 2008 7 11-20. 2 Semenza Gl HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 2007 39 231-234. 3 Derevianko A, D'Amico R, Graeber T, Keeping H, Simms HH Endogenous PMN-derived reactive oxygen intermediates provide feedback regulation on respiratory burst signal transduction. J Leukoc Biol 1997 62 268-276. 4...

Recent Advances in Imaging of Insulinoma and pCell Hyperplasia

Current imaging techniques for the detection of insulinomas in patients with hyperin-sulinemic hypoglycemia include endosonography, which is considered the most sensitive imaging technique, followed by MRI or CT. Somatostatin receptor scintigraphy SRS is a valuable imaging technique in most neuroendocrine tumors of the gastrointestinal tract. In the case of benign insulinomas, however, its value is limited due to the fact that many insulinomas do not express the somatostatin receptor subtypes...

Incretin Mimetics

Exenatide Weight Loss

Exenatide and Its Pharmacological Profile In 1992, exendin-4, a peptide with a 52 amino acid sequence similarity to GLP-1, was isolated from the salivary gland of the lizard Heloderma suspectum Gila monster . Exendin-4 acts as a high potency agonist at the GLP-1 receptor on p cells and the fragment exendin 9-39 is a high potency antagonist 14 . Synthetic recombinant exendin-4 was named exenatide. Exenatide shares all effects of native GLP-1. Figure 4 shows the amino acid sequences of GLP-1,...

DPP and DPP Inhibitors

DPP-4 is a ubiquitous enzyme that can be detected in the endothelium of different organs and that is measurable as circulating enzymatic activity in plasma. Besides GLP-1 and GIP, additional peptides, such as pituitary adenylate cyclase-activating polypeptide PACAP and gastrin-releasing peptide, are substrates of DPP-4 table 2 . However, the affinity of DPP-4 is higher toward GLP-1 than towards other peptides including GIP. DPP-4 cleaves and inactivates GLP-1 within a few minutes 9 . For this...

Diabetes Mellitus and Breast Cancer Risk

Different strategies were used in order to assess the association between diabetes mellitus and breast cancer risk. We divided these studies into three categories 1 studies that evaluated the association between diabetes and breast cancer risk 2 studies that evaluated the association between diabetes and breast cancer mortality, and 3 studies of the association between blood levels of insulin resistance markers, such as glucose or insulin and breast cancer risk. Diabetes Mellitus and Breast...

Carcinogenesis Reconsidered

In healthy tissue, constraints to tumorigenesis exist in the form of hard-wired barriers that prevent disruption of tissue architecture and function by inappropriate cellular proliferation. These controls include highly-regulated activation by specific pro-growth signals and growth-inhibitory barriers through anoikis see below and interactions with other cells and the extracellualr matrix 15-18 . Classical theoretical models focus on these normal tissue controls and propose that carcinogenesis...

Glucose Metabolism Oxidative Phosphorylation versus Aerobe Glycolysis

Krebs Cycle Intermediates Anabolism

However, even once glucose has entered the cell, its fate is not the same when normal tissue is compared to malignant cells. Glucose in healthy cells will be metabolized via the glycolytic pathway until pyruvate see fig. 1, highlighted in light blue , which will be converted into acetyl-CoA, replenishing the concomitant tricarboxylic acid cycle TCA see fig. 1, highlighted in green . The resulting NADH H and FADH2 will further be used in the mitochondrial respiratory chain to recycle ATP from...

Bitter Melon Momordica charantia

Bitter melon M. charantia is a green, bitter vegetable from the gourd family, grown in tropical and subtropical regions throughout the Amazon, East Africa, Asia, the Caribbean, and South America. The slender, climbing vine produces a warty, oblong gourd resembling a small cucumber. Bitter melon is known by many names which include wild cucumber, bitter gourd, balsam apple, balsam pear, ampalaya Philippines , and Kerala India . Clinical conditions for which bitter melon extracts primarily from...

Masur Witten F Thevenod Witten KS Znker Witten

17 figures, 11 in color, and 2 tables, 2008 Basel Freiburg Paris London New York Bangalore Bangkok Shanghai Singapore Tokyo Sydney Founded 1981 by F. Belfiore, Catania Institute of Immunology and Experimental Oncology University of Witten Herdecke Witten, Germany University of Witten Herdecke Witten, Germany Department of Physiology and Pathophysiology Institute of Immunology and Experimental Oncology University of Witten Herdecke Witten, Germany Library of Congress Cataloging-in-Publication...

Vitamin D

Vitamin D is needed to maintain adequate blood levels of insulin. Vitamin D deficiency has been shown to impair insulin synthesis and secretion in humans and in animal models of diabetes. Vitamin D deficiency predisposes individuals to type 1 and type 2 diabetes, and receptors for its activated form - 1a,25-dihydroxyvitamin D3 -have been identified in both 3-cells and immune cells. Serum 25-hydroxyvitamin D levels have been reported to be inversely related to body mass index and body fat...

Acknowledgement

Patrik Rorsman Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK for his continuous interest in my work. 1 Zimmet P, Alberti KG, Shaw J Global and societal implications of the diabetes epidemic. Nature 2001 414 782-787. 2 Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002 415 339-343. 3 Hotamisligil GS The role of TNF-a and TNF...

Failed Adaptation to Insulin Resistance and pCell Failure The Natural History of TD

Normal pancreatic p-cell responds to a chronic fuel excess and obesity-associated insulin resistance with compensatory insulin hypersecretion in order to maintain nor-moglycemia. This adaptive response to insulin resistance involves changes in both function and mass, and is so efficient that normal glucose tolerance is maintained. Longitudinal studies of subjects that develop T2D show a rise in insulin levels in the normoglycemic and prediabetes phases that keep glycemia near normal despite the...

ALipoic Acid

A-Lipoic acid, also known as lipoic acid LA or thioctic acid, and its reduced form, dihydrolipoic acid, are powerful antioxidants. LA scavenges hydroxyl radicals, hypochlorous acid, peroxynitrite, and singlet oxygen. Dihydrolipoic acid also scavenges superoxide and peroxyl radicals and can regenerate thioredoxin, vitamin C, and glutathione, which in turn can recycle vitamin E. There are several possible sources of oxidative stress in diabetes including glycation reactions,...

Info

Ncreased sex hormone production Reduced SHBG production ncreased sex hormone production Reduced SHBG production Increased plasma estrogen, testosterone Increased plasma estrogen, testosterone Increased proliferation, invasiveness, angiogenesis Reduced apoptosis Fig. 2. Mechanisms associating type 2 diabetes and breast cancer. Insulin resistance leads to high plasma insulin concentrations, which activate the extracellular-related-kinase ERK and the AKT pathways through activation of the insulin...