metabolic deregulations in metabolic diseases and cancer

www.nicopillon.com 09/04/2019

Metabolic deregulations in metabolic diseases and cancer

Nicolas J. Pillon, PhD

Department of Physiology and Pharmacology

Karolinska Institutet, Stockholm, Sweden

www.nicopillon.com

Outline

1. Substrate preference and metabolic flexibility

2. Measuring metabolic flexibility in vivo and in vitro

3. Implications of disturbances in metabolic flexibility

4. Associations between metabolic diseases and cancer

5. Prevention of metabolic diseases and cancer


Metabolism is an integrated processAt the whole body level

Apetite regulation

Glucose productionLipogenesis

Insulin secretionGlucagon secretion

Nutriment absorptionIncretin effect

Glucose uptakeLipolysis

Lipogenesis

Glucosereabsorption

Glucose uptakeFatty acid oxidation

Fuel exchange during fastingMeal

Glucagon

↓ Glucose(Glc)

β‐cells

Glc

GlcX

↓ Glucose uptake↓ Glycogenogenesis↑ Neoglucogenesis

GlcFA

Glc FA

↓ Lipogenesis↑ Lipolysis

Glycogen

FA

Intramyocellulartriglycerides

X

X XGlc


Fuel exchange after a mealMeal

Insulin

↑ Glucose(Glc)

↑ Fatty Acids(FA)

β‐cells

Glc

Glc X

↑ Glucose uptake↑ Glycogenogenesis↓ Neoglucogenesis

GlcFA

Glc FA

↑ Lipogenesis↓ Lipolysis

Glycogen(75-80%)

FA

Intramyocellulartriglycerides

↓ Glucose(Glc)

↓ Fatty Acids(FA)

Glc

Progression to type 2 diabetesOral glucose tolerance test

T2DPrediabetesHealthy

Blood glucose (g/L)

1

2

3

4

0 1 2 30

Time (h)Meal

0 1 2 30

Time (h)

Blood In

sulin

(μU/m

L)

40

80

120

160

Meal


Metabolism is an integrated processAt the cellular level

KEGG - Metabolic pathways - Reference pathway

Carbohydrates

Fatty acids

Amino acids

Nutrient uptake and metabolism

https://www.diapedia.org/metabolism-and-hormones/5105765817/metabolic-pathways


Glucose metabolism

Glycolytic intermediates provide the substrates for the pentose phosphate pathway (PPP) that generates the ribose 5-phosphate that is critical for nucleotide biosynthesis. The oxidative arm of the PPP, which utilizes glucose 6-phosphate, additionally generates NADPH. Glycerol 3-phosphate, which contributes the glycerol head groups for phospholipid biosynthesis, is formed from the intermediate dihydroxyacetone phosphate. 3-Phosphoglycerate provides the foundation for the serine synthesis pathway, which can further fuel glycine production for protein synthesis. This pathway also contributes to the pool of one-carbon units (CH2-THF) that are used in nucleotide biosynthesis. Glucose-derived citrate provides the acetyl-CoA that represents the fundamental building block for the synthesis of the fatty acids that comprise cellular lipids. Key metabolic enzymes are shown in blue; NADPH required for biosynthetic reactions is shown in green. CH2-THF, methylene tetrahydrofolate; GLDC, glycine decarboxylase; PHGDH, phosphoglycerate dehydrogenase; PKM2, pyruvate kinase M2 isoform; PPP,pentose phosphate pathway; THF, tetrahydrofolate.

Finley & Thompson. The Metabolism of Cell Growth and Proliferation. The Molecular Basis of Cancer (Fourth Edition) 2015, Pages 191-208.e2

Lipid metabolism

Knobloch. The Role of Lipid Metabolism for Neural Stem Cell Regulation. Brain Plast. 2017 Nov 9;3(1):61-71


Sensing of Fuel and Energy StatusAMP-activated Protein Kinase (AMPK)

Hardie DG, Sakamoto K. AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda). 2006 Feb;21:48-60.

Metabolic changes known to be induced by AMPK in muscle, including stimulation of glucose and fatty acid uptake, fatty acid oxidation, and mitochondrial biogenesis, and inhibition of glycogen synthesis and, via inhibition of TOR, hypertrophyQuestion marks indicate that the direct target for AMPK responsible for the observed downstream effect is not known. The effect on fatty acid uptake has to date only been observed in cardiac muscle.

AMPK activation

• increased uptake of glucose (↑ GLUT4)

• increased oxidation of glucose (↑ HKII)

• Inhibition of glycogen synthesis (↓GS)

• increased uptake of fatty acids (↑ FAT/CD36)

• Increased fatty acid oxidation (↓ ACC)

Modulation of substrate preferenceMechanism of reciprocal inhibition of glucose and fatty acid oxidation

Hue & Taegtmeyer. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E578-91

Mechanism of reciprocal inhibition of glucose and fatty acid oxidation. When glucose uptake and consumption increases, fatty acid oxidation is suppressed by malonyl-CoA’s allosteric inhibition of CPT-1, and increased pyruvate from glycolysis inhibits PDK, which stimulates glucose oxidation (yellow lines). CPT-1 inhibition increases the concentration of LCFA-CoAs, which then are used for triglyceride synthesis and stored (pink arrow). Vice versa, when fatty acid oxidation is high, glucose uptake, glycolysis, and pyruvate oxidation are decreased (red lines) because rising levels of acetyl-CoA and NADH impede PDH activity. Additionally, increased citrate levels inhibit GLUT4 and PFK-1. PFK-1 inhibition results in increased glucose-6-phosphate concentrations that inhibit HK. A decrease in pyruvate oxidation enables pyruvate to be used as either a gluconeogenic precursor or, in energetically demanding tissues, a substrate for PC, which produces oxaloacetate that is used as anapleroticsubstrate (purple arrows). During caloric restriction, the rise in AMP/ATP activates AMPK, which inhibits ACC, stimulating fatty acid uptake by the mitochondria via CPT-1. ACL, ATP-citrate lyase; CACT, carnitine acylcarnitine translocase; CTP, citrate transport protein; CYTO, cytosol; FAS, fatty acid synthase; LCFA, long-chain fatty acid; MITO, mitochondria; MPC, mitochondrial pyruvate carrier; PC, pyruvate carboxylase. Green arrows indicate stimulatory reactions.

From: Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocr Rev. 2018;39(4):489-517. doi:10.1210/er.2017-00211Endocr Rev | Copyright © 2018 Endocrine Society


Metabolic flexibilityThe capacity for an organism to adapt fuel oxidation to fuel availability

The ability to switch from one substrate to another is crucial to maintain whole body energy balance and a healthy storage of energy.

Goodpaster BH, Sparks LM. Metabolic Flexibility in Health and Disease. Cell Metab. 2017 May 2;25(5):1027-1036.

Metabolic flexibilityThe capacity for an organism to adapt fuel oxidation to fuel availability

The primary purpose of the substrate shift is to move from catabolic to anabolic processes.

Insulin is a major driver of this shift.

Energy is stored after nutrient intake (glycogen, TG).Stored energy is restituted during fasting.

Inappropriate storage leads to ectopic lipid accumulation in non-adipose tissues (lipotoxicity),

that contributes to T2D and its complications.

Catabolism Anabolism

Lipids

Carbohydrates


MEASURING METABOLIC FLEXIBILITYIN VIVO AND IN VITRO

Methodology

Measuring Energy Sources in vivoCalorimetry

Cageor

Chamber

Oxygen in (VO2i)

Carbon Dioxide in (VCO2i)

Oxygen out (VO2o)

Carbon dioxide out (VCO2o)

Promethion CagesSable Systems International

Maastrich Instruments BV Dual Chamber Whole Body Calorimeter

Cosmed Desktop Metabolic System for Indirect Calorimetry with Mask

2 2 2

2

2

2 2 2


The source of energy dictates the amount of O2 requiredto oxidize the carbons and hydrogens into CO2

Measuring Energy Sources in vivoRespiratory Exchange Ratio = Respiratory Quotient

Emily K. Sims et al. Am J Physiol Endocrinol Metab. 2013 Dec;305(12):E1495-511.

2

2

Carbohydrate (Glucose)

C6H12O6 + 6O2 → 6CO2 + 6H2O + 38ATP

Fat (Palmitate)

C16H32O2 + 23O2 → 16CO2 + 16H2O + 129ATP

RER = 16.CO2 ÷ 23.O2 = 0.7

RER = 6.CO2 ÷ 6.O2 = 1

Measuring Energy Sources in vivoRespiratory Exchange Ratio = Respiratory Quotient

Breakfast A Breakfast B

2 3 4 5 6 7 8 9 10 11 120.6

0.7

0.8

0.9

1.0

Time

RE

R

2 3 4 5 6 7 8 9 10 11 120.6

0.7

0.8

0.9

1.0

Time

RE

R


Measuring substrate preference in vitroSeahorse technology – standard use

Measuring substrate preference in vitroSeahorse technology – XF Glycolysis Stress Test Kit


Measuring substrate preference in vitroSeahorse technology – XT Mito Fuel Flex Test

WHY DOES IT MATTERS?


Metabolic flexibility is impaired in individuals with type 2 diabetes

Galgani, Moro & Ravussin. Metabolic flexibility and insulin resistance. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1009-17.Apostolopoulou et al. Metabolic flexibility and oxidative capacity associate with insulin sensitivity in individuals with type 2 diabetes. Diabetologia. 2016 Oct;59(10):2203-7.

● Metabolically flexible

○ Metabolically inflexible (T2D)

Metabolic flexibility is enhanced in athletes

Dube et al. Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance. Am. J. Physiol. Endocrinol. Metab. 307, E1117–E1124.

Trained subjects more effectively decrease glucose

uptake and increase fatty acid oxidation than

untrained individuals.

Healthy trained muscle can rapidly switch

between fuels

Glucose uptake Fatty acid oxidation

light bars: control

dark bars: co-infusion of intralipid


Substrate preference regulates immune cell polarization

Blagih & Jones. Polarizing Macrophages through Reprogramming of Glucose Metabolism. Cell Metab. Volume 15, Issue 6, 6 June 2012Smith et al. Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocr Rev. 2018 Aug 1;39(4):489-517

Stimulated lymphocytes and macrophages engage in glycolysis and glutaminolysis augmented rates of glycolytic flux and regeneration of NAD+. biosynthesis of nucleotides, amino

acids, and lipids

LPS-stimulated monocytes switch from OXPHOS to glycolysis increased glucose consumption, lactate production, and NAD+/NADH ratio

Fatty acid transport protein 1 knockout mice fed high-fat diets showed an increased proinflammatory phenotype and worsened metabolic syndrome


Geeraerts et al. Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity. Front. Immunol., 15 March 2017



Geeraerts et al. Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity. Front. Immunol., 15 March 2017

Modulation of substrate preference is crucialfor proliferation/differentiation

Vander Heiden et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029-33.


Metabolic flexibility in cancer

Cancer cells typically exhibit:

(1) deregulated uptake of glucose and amino acids

(2) use of opportunistic modes of nutrient acquisition

(3) use of glycolysis/TCA cycle intermediates for biosynthesis and reduced NADPH production

(4) increased demand for nitrogen

(5) alterations in metabolite-driven gene regulation

(6) specialized metabolic interactions with the microenvironment

.

Reliance of glycolysis is highly variable depending the cancer cell line Metastatic phenotype suggest that tumor cells do not become metabolically hardwired but remain

able to reroute metabolism to adapt to their phenotype and the newly acquired environment

Herst. Cell hierarchy, metabolic flexibility and systems approaches to cancer treatment. Curr Pharm Curr Pharm Biotechnol. 2013;14(3):289-99.

Glycolysis in cancer cells

It is misleading to use glucose uptake and lactate production alone to estimate aerobic glycolysisThe increased glycolysis might be a reflection of the cells adapting to their environment

100 glucose

5%

aerobic respiration32 ATP/glucose

160 ATP45% of total ATP

95%

aerobic glycolysis 2 ATP/glucose

190 ATP55% of total ATP

Lactate

Glutamate

Fatty acids

Lactate



Constitutive activation of PI3K/Akt signalling addicts tumour cells to glucose by interfering with the induction of fatty acid oxidation when glucose is withdrawn

Shiojima & Walsh. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev. 2006 Dec 15;20(24):3347-65.


c-Myc addicts cells to glutamine by preventing them from supplying the tricarboxylic acid cycle using other nutrients

Chen & Cui. Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach. Int J Mol Sci. 2015 Sep 22;16(9):22830-55.



Metabolic gene expression of cancer cells more closely resembles that of the parental tissue than it does of other cancers

Where tumour cells reside along the spectrum of metabolic flexibility/rigidity may well determine their sensitivity to therapy.

Olson. Pyruvate and metabolic flexibility: illuminating a path toward selective cancer therapies. Trends Biochem Sci. 2016 Mar;41(3):219-230.Mayers & Vander Heiden. Nature and Nurture: What Determines Tumor Metabolic Phenotypes? Cancer Res. 2017 Jun 15;77(12):3131-3134.

ASSOCIATION BETWEEN METABOLIC DISEASES AND CANCER

Epidemiology


WHO facts

Diabetes mellitus High blood glucose kills about 3.4 million

people annually

415 million people have diabetes globally

Cost >$1.3 trillion/year globally

Main risk factors for diabetes are behavioural and dietary risks: high body mass index, unhealthy diet, physical inactivity, tobacco use

Type 2 diabetes is prevented or delayed by modifying diet and increasing physical activity

Cancer Cancer killed 9.6 million people worldwide

in 2018

Second leading cause of death globally

Cost >$1.2 trillion/year globally

Main risk factors for cancer are behavioural and dietary risks: high body mass index, low fruit and vegetable intake, physical inactivity, tobacco and alcohol use

Between 30% and 50% of cancer deaths could be prevented by modifying or avoiding key risk factors

Both are on the rise!

Prevalence of diabetesFasting Blood Glucose ≥ 7mM, ages 18+, males, 2014


Prevalence of overweightBody Mass index ≥ 25kg/m2, ages 18+, males, 2014

Cancers associated with Overweight and Obesity

Cancer.gov/obesity-fact-sheet

•Endometrial cancer: 2-7 times as likely•Esophageal adenocarcinoma: 2-4 times as likely•Gastric cardia cancer: twice as likely•Liver cancer: twice as likely. Association stronger in men.•Kidney cancer: twice as likely •Multiple myeloma: slight increase in risk (10-20%)•Meningioma: risk increased by 20-50%•Pancreatic cancer: risk increased by 50%•Colorectal cancer: slightly more likely (about 30%).•Gallbladder cancer: slight increase in risk (about 20-60%). Association greater in women•Breast cancer: In postmenopausal women, higher BMI is associated with a modest increase in risk (20-40%). In premenopausal women, overweight and obesity are associated with a 20% decreased risk. Obesity is also a risk factor for breast cancer in men. •Ovarian cancer: slight increase (5%) in risk.•Thyroid cancer: slight increase in risk (10%)


Cancers associated with diabetes

AIMS/HYPOTHESIS: Diabetes has been shown to be a risk factor for some cancers. Whether diabetes confers the same excess risk of cancer, overall and by site, in women and men is unknown.METHODS: A systematic search was performed in PubMed for cohort studies published up to December 2016. Selected studies reported sex-specific relative risk (RR) estimates for the association between diabetes and cancer adjusted at least for age in both sexes. Random-effects meta-analyses with inverse-variance weighting were used to obtain pooled sex-specific RRs and women-to-men ratios of RRs (RRRs) for all-site and site-specific cancers.RESULTS: Data on all-site cancer events (incident or fatal only) were available from 121 cohorts (19,239,302 individuals; 1,082,592 events). The pooled adjusted RR for all-site cancer associated with diabetes was 1.27 (95% CI 1.21, 1.32) in women and 1.19 (1.13, 1.25) in men. Women with diabetes had ~6% greater risk compared with men with diabetes (the pooled RRR was 1.06, 95% CI 1.03, 1.09). Corresponding pooled RRRs were 1.10 (1.07, 1.13) for all-site cancer incidence and 1.03 (0.99, 1.06) for all-site cancer mortality. Diabetes also conferred a significantly greater RR in women than men for oral, stomach and kidney cancer, and for leukaemia, but a lower RR for liver cancer.CONCLUSIONS/INTERPRETATION: Diabetes is a risk factor for all-site cancer for both women and men, but the excess risk of cancer associated with diabetes is slightly greater for women than men. The direction and magnitude of sex differences varies by location of the cancer.

Cancer risk is increased with diabetes

Women Men


Cancers associated with type 2 diabetesMeta-analyses, 2005-2011

• Higher incidence of various types of cancer among individuals with diabetes, particularly type 2 diabetes

• People with diabetes have poorer survival than non-diabetics after a diagnosis of cancer.

• Association with diabetes varies in important respects between cancer types

https://www.diapedia.org/associated-disorders/6104460119/epidemiology-of-cancer-and-diabetes

Association of metabolic diseases with cancersBiologic plausibility

• Hyperglycemia (i.e., high glycose levels). Availability of glucose fuels cancer cells that typically rely on glucose for metabolism.

• Chronic inflammation. Diabetes and obesity are associated with chronic activation of the immune system in tissues promoting a tumour-prone environment.

• Hyperinsulinemia (i.e., high insulin levels). Insulin promotes the growth of cancer cells, which typically express the insulin receptor.

• In obese individuals, adipose tissue produces excess amounts of estrogen, high levels of which have been associated with increased risks of breast, endometrial, ovarian, and some other cancers.

• Fat cells produce hormones regulating cell growth. Leptin promotes cell proliferation, while adiponectin may have antiproliferative effects.

https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet


Association of metabolic diseases with cancersBiologic plausibility - hyperglycemia

Johnson JA, Bowker SL. Intensive glycemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. Diabetologia 2011;54:25–31

Cancer cells rely on glucose for metabolism, hyperglycemia provides extra energy.

Hyperglycemia activates many pathways related to cell proliferation and apoptosis. High glucose decreases E-Cadherin, stimulated epidermal growth factor signalling, modulates the AMPK/mTOR/S6 and MAPK pathways, etc.

Hyperglycemia damages tissues through repeated changes in glucose metabolism and accumulation of glycated biomolecules (AGE).

RAGE expression is associated with metastatic ability of pancreatic cancer cells and with glioma growth and metastasis through MAPK activation and MMP-2/9 induction.

BUT Clinical trials of glucose-lowering therapies in type 2 diabetes has shown no diminution of cancer risk

Association of metabolic diseases with cancersBiologic plausibility – Chronic inflammation

• Diabetes and obesity are associated with chronic activation of the immune system in tissues promoting a tumour-prone environment.

• Production of free radicals can disrupt signaling and damage DNA.

• IL-6 and TNF-α induce genes promoting proliferation and inhibiting apoptosis by upregulating the transcription factor, NF-кB

• Elevated levels of IL-6, TNF-α, and C-reactive protein linked to greater risks for colorectal and breast cancer

• Chronic local inflammation induced by gastroesophageal reflux is a cause of esophagealadenocarcinoma.

• Hepatitis are risk factors for different types of liver cancer.

Kwon et al. Genetic polymorphisms in inflammation pathway genes and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2011 May;20(5):923-33.


Association of metabolic diseases with cancersBiologic plausibility - estrogen

• In obese individuals, adipose tissue produces excess amounts of estrogen, high levels of which have been associated with increased risks of breast, endometrial, ovarian, and some other cancers.

• Estrogens seem to support tumor development and progression through direct effects on induction of cellular proliferation and inhibition of apoptosis via ER-α agonism

• secretion of vascular endothelial growth factor and angiogenesis

Wada et al. New insights into metabolic regulation via bifurcated function of estrogen receptor α. Diabetes. 2013 Dec;62(12):3996-8.

Association of metabolic diseases with cancersBiologic plausibility - adipokines

• Fat cells produce hormones regulating cell growth.

• Leptin promotes cell proliferation through the STAT3 pathway

• Adiponectin has antiproliferative effects through AMPK

D. Housa, J. Housova, Z. Vernerova, M. Haluzik, Adipocytokines and cancer. Physiol. Res. 55, 233–244 (2006)Chang et al. Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression. Cancer Res. 2015 Jun 1;75(11):2375-2386.


Association of metabolic diseases with cancersBiologic plausibility - Hyperinsulinemia

• In obesity and diabetes, the pancreas oversecretes insulin to compensate for insulin resistance.

• Insulin promotes the growth of cancer cells, which typically express the insulin receptor.

• Chronic hyperinsulinemia reduces IGF binding proteins which result in increased tissue availability of both IGF-I and IGF-II.

• interfering ratios between insulin andIGF-1 can manipulate tumorigenesis in animal models, suggestingthat insulin/IGF signaling positively contributes to tumorigenesisin obese animals

• Ras/Raf/MAPK and PI3K/Akt/mTOR pathways

https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet

Association of metabolic diseases with cancersRegulatory mechanisms

Chang & Yang. Hyperglycemia, tumorigenesis, and chronic inflammation. Crit Rev Oncol Hematol. 2016 Dec;108:146-153.


PREVENTION OF METABOLIC DISEASES AND CANCERS

Association of metabolic diseases with cancersDiet regulates (almost) everything

Diet-hypercaloric

-high saturated fat-high refined food

-low fiber

Chronic inflammationHyperinsulinemiaHyperglycaemia

AdipokinesSex hormones

Cancer

ObesityDiabetes

Adapted from Scappaticcio et al. Endocrine. 2017 May;56(2):231-239


Caloric restriction and cancerAnimal studies

Chen et al. Effect of Intermittent versus Chronic Calorie Restriction on Tumor Incidence: A Systematic Review. Sci Rep. 2016 Sep 22;6:33739.Longo & Fontana. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci. 2010 Feb;31(2):89-98.

Prevalence of physical inactivityModerate intensity ≤150 min/week, ages 18+, males 2010


Exercise & diet interventions preventthe development of diabetes

Diabetes Prevention Program Research Group. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention. N Engl J Med 2002; 346:393-403

BMI>24, impaired glucose tolerance (pre-diabetes). Randomly assigned to one of three interventions: standard lifestyle recommendations plus metformin (Glucophage) at a dose of 850 mg twice daily, standard lifestyle recommendations plus placebo twice daily, or an intensive program of lifestyle modification. Lifestyle intervention was healthy low-calorie, low-fat diet and physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week.

CONCLUSIONS. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.

BUT the goal was at least a 7 percent weight loss with a drastic diet in addition to exercise…

Exercise is associated with lower cancer mortality

Scott et al. Association of Exercise With Mortality in Adult Survivors of Childhood Cancer. JAMA Oncol. 2018 Oct 1;4(10):1352-1358.Patterson et al. Sedentary behaviour and risk of all-cause, cardiovascular and cancer mortality, and incident type 2 diabetes. Eur J Epidemiol. 2018 Sep;33(9):811-829.

Relative risk of cancer Mortalityand Total Sedentary Behaviour

Rel

ativ

e ri

sk –

Can

cer

Mo

rtal

ity

Total Sedentary Behaviour (hrs/day)

Recurrent or progression of primary disease mortality in adults survivors of childhood cancer

Time since Baseline years

Cu

mu

lati

ve in

cid

ence

, %

1.4

0 4 8 12 16

5

4

3

2

1

0 5 10 15 20

1.2

1.1

1.0

1.3


What can we do?

Education and Prevention: adjust diet, ↑exercise, ↓smoking, ↓alcohol

Policies on environmental factors: pollution, junk food

Research and Treatment: more precise therapies

Would reduce the incidence of both metabolic disease and many cancers

References

Scappaticcio et al. Insights into the relationships between diabetes, prediabetes, and cancer. Endocrine. 2017 May;56(2):231-239.

Chang & Yang. Hyperglycemia, tumorigenesis, and chronic inflammation. Crit Rev Oncol Hematol. 2016 Dec;108:146-153.

Kwon et al. Genetic polymorphisms in inflammation pathway genes and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2011 May;20(5):923-33.

Chang et al. Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression. Cancer Res. 2015 Jun 1;75(11):2375-2386.

D. Housa, J. Housova, Z. Vernerova, M. Haluzik, Adipocytokines and cancer. Physiol. Res. 55, 233–244 (2006)

Kim et al. Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol Endocrinol. 2010 Jul;24(7):1441-52.

Wada et al. New insights into metabolic regulation via bifurcated function of estrogen receptor α. Diabetes. 2013 Dec;62(12):3996-8.

Smith et al. Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. EndocrRev. 2018 Aug 1;39(4):489-517.

Hardie DG, Sakamoto K. AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda). 2006 Feb;21:48-60.

Finley & Thompson. The Metabolism of Cell Growth and Proliferation. The Molecular Basis of Cancer (Fourth Edition) 2015, Pages 191-208.e2


Doctoral education - VT19Experimental techniques in study of metabolic and endocrine disorders

Title Experimental techniques in study of metabolic and endocrine disorders

Course number 1559

Programme Metabolism och endokrinologi

Language English

Date 2018-11-26 -- 2018-11-30

Purpose of the courseThis course will enable the doctoral student to acquire the necessary knowledge to address experimentally key points of metabolic characterization of experimental models in diabetes research.

Intended learning outcomes

After the course the students will be able i) to measure glucose transport in isolated rodent skeletal muscle; ii) to measure lipolysis in isolated adipocytes; iii) to dissect out mouse pancreatic islets and measure the insulin release; iv) tojudge and analyze obtained data. The students will also be able to describe the possibilities and limitations of the above techniques.

Contents of the course

The course is laboratory based, aiming to give all participants hands on experience with isolation of pancreatic islets, skeletal muscle and adipose tissue. Techniques for measurement of glucose transport in isolated rodent skeletal muscle, of lipolysis in isolated adipocytes, and for studying insulin release from pancreatic islets will be covered. Theoretical andpractical considerations will be presented and discussed.

Teaching and learning activities

The course meets for five days full time, including three full day laboratory practical sessions. The first day will consist of several lectures to give a background to the metabolic questions which will be addressed in the practical part of the course. Our aim is to provide the student with a hands on experience of each technique covered. In order to achieve this, for the laboratory work the course participants will be subdivided into smaller groups.

Literature and other teaching material Scientific publications covering the techniques covered will be distributed at the start of the course.

Course responsible Alexander Chibalin, [email protected]

metabolic deregulations in metabolic diseases and cancer

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