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Obesity and diabetes: visible sign of an invisible threat

Michael Rennie
PhD FRSE
Symers Professor of Physiology
Division of Molecular Physiology
School of Life Sciences
University of Dundee
E:m.j.rennie@dundee.ac.uk

The incidence of obesity is increasing in all developed countries, the leader being the USA, where approximately 55% of the population is now defined as overweight or obese.(1) However, the UK is catching up fast. The House of Commons Public Accounts Committee reported in January 2002 that most adults in Britain were already overweight and 20% were obese. This costs the economy and the NHS £2.5 billion/year - and is responsible for as many as 30,000 deaths/year, according to the Chairman of the Public Accounts Committee, Edward Leigh MP.
The increase is fastest among children. The proportion of British boys and girls who are overweight has roughly doubled in the past 10 years, although a greater proportion of girls were already overweight 10 years ago. Currently about 2% of English boys and 3% of English girls are obese. Experience in the USA suggests that three-quarters of overweight children aged between 10 and 13 years will become overweight and obese as adults. Children who are obese are much more likely as adults to develop hypertension, hyperlipidaemia, hyperinsulinaemia, coronary artery disease and type 2 diabetes than lean children.(2,3) In the USA, the doubling in the prevalence of childhood obesity between 1982 and 1994 was associated with a 10-fold increase in the incidence of type 2 diabetes,(4) which itself increases the risk of developing cardiovascular disease.
The incidence of type 2 diabetes is greater among certain ethnic groups such as Mexican Americans, native Americans, south Asians and Americans of African descent, but traditionally it has been a disease of adulthood. However, recently alarm bells rang in Britain when the first cases of type 2 diabetes were reported in obese south Asian children, and soon after in obese white children, in the UK.(5)
An important study by Sinha and colleagues, recently published in the New England Journal of Medicine, demonstrated that among obese children and adolescents in the USA, 21-25% between the ages of 4 and 18  years showed impaired glucose tolerance, insulin resistance, and increased concentrations of insulin and C-peptide in the blood after an overnight fast.(6)

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What is the link between diabetes and obesity?
The name "diabetes mellitus" comes from the Latin words for a "syphon" and "sweet", referring to the symptoms of overproduction of urine that contains glucose. Glucose overflows into the urine when its concentration in the blood is about two to three times the normal level, as a result of either a lack of the hormone insulin or an inability of the tissues to respond adequately to insulin. Insulin, which is secreted in response to glucose in the blood, is normally responsible for stimulating the transport of glucose into muscle and adipose tissue. In type 1 diabetes the pancreas, which normally produces insulin, no longer does so. In type 2 diabetes, tissues that would normally respond by storing glucose, such as skeletal muscle, become insulin insensitive or resistant. Both cases result in a rise in blood glucose concentration. In type 2 diabetes, paradoxically, insulin concentrations usually also rise, stimulated by increased blood glucose - as though the body were attempting to overcome the insulin resistance by making more insulin available. This high insulin concentration stimulates glucose uptake into fat, especially around the viscera, but is unable to overcome the insulin resistance of muscle.
The cause of type 1 diabetes - the destruction of the insulin-secreting cells of the pancreas ­- is not well understood, although there have been suggestions that it is viral in origin, and that those with some genetic susceptibility are most at risk. In contrast, we know that there is a strong and apparently causal association between being overweight and developing insulin insensitivity (ie, glucose intolerance), which may lead to hyperglycaemia, hyperinsulinaemia and ultimately a failure of the pancreas - when the type 2 diabetes effectively becomes type 1 diabetes. The risk of developing associated cardiovascular disease and hypertension in patients with type 2 diabetes is markedly increased by obesity.

The link between obesity, diabetes and perinatal programming
The pioneering studies of Barker and Hales highlighted the fact that low birth weight can predispose to later insulin resistance and hyperinsulinaemia.(7) Community health teams need to ensure that pregnant women eat adequately to support the growth of their baby and also advise them to breastfeed, since bottle feeding is associated with an increase in infant obesity.

Treatment of obesity

Diet and exercise
Adults  Although there is a genetic predisposition to type 2 diabetes among obese individuals from certain ethnic groups, obesity per se is a major trigger: the explosion in the incidence of obesity points strongly towards overeating and lack of exercise as the major causes. Weight reduction should be a major target. Simply eating less is a poor strategy for weight loss. Even total starvation with the maintenance of normal physical exercise equivalent to 4-5MJ/day would cause a loss of only 100g of fat/day in an adult, and run the risk of causing a fall in the basal metabolic rate due to decreased thyroid hormone activity. Weight loss of about 1-2kg/week is best achieved by increasing physical activity as well as decreasing dietary intake. An increase in physical activity benefits patients with type 2 diabetes because exercise itself increases the insulin sensitivity of the tissues, particularly muscle tissue but also surprisingly liver tissue.
Children  While treatment of obesity in adults, who often have greater motivation and greater control of their lives, is difficult, evidence from the USA suggests that halting the development of obesity in children once it has started is even more difficult. It is also expensive and requires a very high degree of motivation from the affected child. With children, prevention is likely to be more successful than treatment. These are often uncomfortable facts for parents to accept, many of whom have passed on their unhealthy eating habits to their children.
A child's growth should ideally be monitored using the BMI (body mass index) and behavioural strategies adopted to establish healthy eating habits and ­maintenance of physical activity.(8)
Maintaining weight loss is difficult and often requires a substantial amount of support from the family and members of the community health team.

Pharmacological approaches to treatment of obesity in patients with type 2 diabetes
The UK National Institute for Clinical Excellence (NICE) acknowledges a need for the use of drugs in patients with type 2 diabetes. Orlistat is a compound that inhibits pancreatic lipase activity in the small intestine so that fatty food is not digested and its energy becomes unavailable to the body. Preliminary results of clinical trials of orlistat in the USA suggest that it is effective in controlling energy intake, but unless physical activity increases to increase energy expenditure, the rate of weight loss is low. Furthermore, there are unpleasant side-effects, such as flatulence, bloating and staining of underwear, and long-term use is associated with the development of vitamin A and D deficiency (which can be cured by supplementation).
Sibutramine is a drug that interferes with central noradrenergic and serotonergic mechanisms and claims to decrease appetite by directly inhibiting the hypothalamic drive to eat. Because the side-effects of sibutramine include an increase in blood pressure and heart rate, the drug should not be used in patients with hypertension or coronary vascular disease.
It is not considered wise to use pharmacological approaches to limit food intake in children.

Pharmacological treatment of type 2 diabetes in obese patients
This follows the same pattern as in obese patients: attempt to use oral hypoglycaemic agents (sulphonylureas, biguanides and troglitazones), in conjunction with decreasing dietary intake of fat and refined sugars and increasing exercise. The use of insulin should be left as a last resort. The combination of exercise and oral hypoglycaemic agents appears to be very successful. The new troglitazone oral therapies look particularly promising.(10-12)

Exercise and type 2 diabetes
Exercise has benefits beyond weight loss in obese and overweight people with type 2 diabetes. The metabolic effects of exercise on muscle, the liver, the pancreas and abdominal adipose tissue are remarkably quick to develop. Even a single bout of moderate-intensity exercise can increase glucose tolerance for a day, and a few weeks of regular exercise can rejuvenate the glucose-handling capacity of overweight men and women in their 60s and 70s - so it is never too late to obtain the benefits.(13) It seems likely that exercise is in fact more effective than metformin in the treatment of type 2 diabetes, and of course it is much cheaper to prescribe.(14) A good clinical guide to the benefits of exercise and its application as a therapy is provided in a recent review by Professor Ed Horton and colleagues from the famous Joslin Clinic in Boston.(15)

The final word
In a recent editorial in the New England Journal of Medicine,(16) Prof Albert Rocchini proposed that the most cost-effective method of treating children is to identify those obese children who are at high risk of developing diabetes. This can be done by measuring the fasting insulin to glucose ratio or by application of an oral glucose tolerance test. These children are subsequently targeted for intensive treatment both for obesity and for diabetes. For adults with type 2 diabetes, treatment with oral hypoglycaemic agents together with the ­control of diet and physical activity appears to be the treatment of choice.

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References

  1. The practical guide: identification, evaluation and treatment of overweight and obesity in adults. Available from URL: http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm
  2. Freedman DS, Khan LK, Dietz WH, Srinivasan SR, Berenson GS. Relationship of childhood obesity to coronary heart disease factors in ­adulthood: the Bogalusa Heart Study. Paediatrics 2001;108:712-8.
  3. Strauss RS, Pollack HA. Epidemic increase in childhood overweight 1986-1998. JAMA 2001;286:2845-8.
  4. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khouri YPR, Ziegler P. Increased incidence of non-insulin-dependent diabetes ­mellitus among adolescents. J Paediatr 1996;128:608-15.
  5. Drake AJ, Smith A, Betts R, Crown EC, Shield JP. Type 2 diabetes in obese white children. Arch Dis Child 2002;86:207-8.
  6. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose ­tolerance among children and ­adolescents with marked obesity. N Engl J Med 2002;346:802-10.
  7. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001;60:5-20.
  8. Mackenzie NR. Childhood obesity: strategies for prevention. Paediatr Nurs 2000;26:527-30.
  9. Rosenbloom AL. Increasing ­incidence of type 2 diabetes in children and adolescents: treatment consideration. Paediatr Drugs 2002;4:209-21.
  10. Ehtishan S, Barrett TG, Shaw MJ. Type 2 diabetes mellitus in UK children - an emerging problem. Diabet Med 2000;17:867-71.
  11. Inzucchi SE. Oral anti-­hyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287:360-72.
  12. Reasner CA II. Promising new approaches. Diabet Obes Metab 1999;1 Suppl 1:S41-8.
  13. Kirwan JP, Kohrt WM, Wojta DM, Bourey RE, Holloszy JO. Endurance exercise training reduces glucose-­stimulated insulin levels in 60- to 70-year-old men and women. J Gerontol 1993;48:M84-90.
  14. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the ­incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
  15. Hamdy O, Goodyear LJ, Horton ES. Diet and exercise in type 2 diabetes mellitus. Endocrinol Metab Clin North Am 2001;30:883-907.
  16. Rocchini AP. Childhood obesity and a diabetes epidemic. N Engl J Med 2002;346:854-5.

Resources
National Audit Office (NAO). Tackling obesity in England. London: HMSO; 2001. (price £11, or download from NAO website) W:www.nao.gov.uk/pn/00-01/0001220. htm
Association for Study of Obesity
W:www.aso.org.uk
Management of Type 2 diabetes (Therapeutics Lett 1998;23) W:www.ti.ubc.ca/pages/letter23.htm
Children with Diabetes
(online community for kids, families and adults with diabetes)
W:www.castleweb.com/diabetes/
BMI for Kids (guidelines from US National Center for Chronic Disease Prevention and Health Promotion)
http://128.248.232.56/CDCGrowth/presentation/
US Centers for Disease Control (excellent website on diabetes)
W:www.cdc.gov/diabetes/
Diabetes National Service Framework
W:www.doh.gov.uk/nsf/diabetes/

Forthcoming events
24 July 2002
British Association for Psycho-pharmacology annual summer meeting Harrogate (will contain a ­symposium ­entitled "The Psycho-pharmacology of drug-induced weight gain")
For more ­information: W:www.bap.org.uk
Primary Care Diabetes UK regional ­conferences
(events aimed at all healthcare ­professionals working with people with diabetes, giving  an opportunity to gather information on the latest developments in diabetes care, discuss current issues, attend workshop sessions and network with colleagues)
W:www.diabetes.org.uk/conferences/primary.htm