Genetics and environmental factors in obesity and diabetes: Complex problems, complex solutions

Abstract

Over the centuries people have become taller, heavier, and stronger. One of the major reasons for this is the increasing supply of calories in our diets. In earlier times, weight gain was extremely beneficial for health, well-being, and lifespan, but in 2012 we are at a point where weight gain has gone too far and is now detrimental. We are facing an overeating epidemic and the adverse health effects of obesity. This article discusses some of the causes of obesity and the factors affecting it.

Keywords:

• Obesity
• Environmental factors
• Genetic factors
• Obesity-related diseases
• Type 2 diabetes

Clinical pharmacology series

Obesity

A growing problem…

Obesity is now a global phenomenon. It has reached epidemic proportions; almost a billion adults are overweight and one-third of these individuals can be classified as clinically obese (BMI ≥ 30 kg/m²). In the USA the age-adjusted prevalence of obesity is 33.8% overall. Obesity can result in pathophysiological changes in regional blood flow, lean mass and an increase in fat mass. A recent review discussed the implications of obesity for drug therapy¹. Alterations to pharmacokinetics (PK) and pharmacodynamics (PD) and any consequent requirement for dose adjustment were investigated. The authors summarised that obesity had greatest effect on the absorption of drugs given parenterally. Drug distribution was likely to be affected by changes in the volume of distribution, tissue perfusion and plasma protein binding. Both CYP and Phase II- mediated drug metabolism were altered by obesity. For drugs that were renally excreted, increased weight led to difficulties in calculating glomerular filtration rate (GFR). Additionally, GFR plus tubular secretion and reabsorption were altered in obesity. Overall, it was concluded that the changes in drug disposition in obese populations are highly variable and dependent on several factors, including drug characteristics, degree of obesity and patient-specific organ function.

A review of drug product labels and approval packages found limited information on dosing guidance in obese patients. It was recommended that the evaluation of PK and PD in obese populations become incorporated into the general drug development process.

In children

An increase in obesity has also been recorded in the paediatric population. A US report found the prevalence of obesity to be 17% in the age group 2–19 years. The consequences of obesity in this population for the disposition of drugs is less well studied compared with adults. Nevertheless, studies are starting to appear in the literature. A recent investigation examined whether obese and healthy-weight children vary with respect to drug metabolising enzyme activity². The activity of the oxidative enzymes CYP1A2 and xanthine oxidase (XO) were studied along with the conjugative enzyme activity of N-acetyltransferase 2 (NAT2). No difference was observed in CYP1A2 activity. For both XO and NAT2 enzyme activity was elevated in the obese population. These findings mirrored results found in adults. It was concluded that further studies were required in the obese paediatric population, in order to determine the clinical consequences on dosage for drugs that are metabolised by these enzymes.

Drug Development

Clinical pharmacology aims to ensure that the right dose is given to the right patient at the right time. To do this an understanding is required of the inherent variability present in any patient population and the effect that it may have on drug response. Clearly obesity is a factor that may alter the PK/PD response and the consequent therapeutic dose. Given its prevalence obesity provides a further challenge for the drug innovator!

Graham Blakey

GBPK Consulting Ltd

[email protected]

http://www.gbpkconsulting.co.uk

Additional information

Notes on contributors

Melanie Price

Melanie Price is a molecular biologist with a BSc in Biochemistry and a PhD in Molecular Genetics. She is currently researching in neuroscience and editing scientific and medical manuscripts as a freelance scientific writer. Melanie joined EMWA in 2009 and participates in their extensive and interesting medical writing workshops.

Diana Raffelsbauer

Diana Raffelsbauer is a freelance medical writer, journalist, and translator. She has an MSc in Biology and a PhD in Medical Microbiology. She has been a member of EMWA since 2007. In 2011, she founded PharmaWrite Medical Communications Network, a network of freelancers providing services in different areas of medical writing, journalism, and translations in various European languages.