Obesity

Type 2 diabetes and obesity are so closely linked that it is almost impossible to consider these two conditions in isolation. The prevalence of obesity has risen steadily around the world for the last 30 – 40 years and has inevitably been followed by increases in type 2 diabetes. However, there are clearly differences between populations with some ethnic groups such as Europids being relatively protected from the effects of obesity upon diabetes, whereas some populations (for example those from some Pacific Islands, Pima Indians and some from Asia and Africa) seem exceptionally sensitive to modest increases in body weight. As a result much of the burden of type 2 diabetes is falling on the developing world. Obesity itself has a complex aetiology; the recent increases are certainly a result of adverse environmental change (easy availability of energy dense food, accompanied by a marked fall in habitual physical activity), but for individuals their underlying genetic background, and in some cases factors such as drugs or damage to the biological systems that regulate energy balance can be an overriding influence.

Background

The mechanisms by which obesity leads to the development of type 2 diabetes are complex and incompletely understood. Diabetes is characterised by insulin resistance, but hyperglycaemia only develops when insulin secretion fails to keep up with the increased demands placed on the beta-cells because of insulin resistance.

Insulin resistance is associated with a more central distribution of body fat, although this may also be a marker for deposition of fat in organs other than adipose tissue, notably liver and muscle, but also including the pancreas. Increased fat may result in insulin resistance as a result of increased circulation of non-esterified (‘free’) fatty acids which can compete for glucose for metabolism; this may be exacerbated in more sedentary individuals.

People with higher fat mass also have evidence of a systematic inflammatory response. This may be driven by cell death in hypoxic fat depots – the resultant inflammatory response could contribute further to the development of insulin resistance as release of pro-inflammatory cytokines such as interleukin-6 and tumour necrosis factor alpha (TNFα) can interfere with insulin signalling. Such processes may also contribute to beta-cell failure; ectopic fat is present in the pancreas and pancreatic islets and may contribute to beta-cell dysfunction and ultimately beta-cell death.

Other (most likely secondary) abnormalities that may contribute to the pathophysiology of type 2 diabetes in obesity include changes in gut hormone (especially incretin) secretion, alterations in CNS driven autonomic function that may impair insulin secretion and hepatic glucose production, and hyperglycaemia driven increases in renal glucose reabsorption.

An important consequence of insulin resistance is development of dyslipidaemia, particularly increased triglycerides and low HDL cholesterol. Blood pressure can also rise as a result of insulin resistance, sodium retention and increased vascular resistance in obesity. The combination of central adiposity, insulin resistance, hyperglycaemia, dyslipidaemia and hypertension is termed the metabolic syndrome.

Obstructive sleep apnoea is an important consequence of obesity and has been associated with an increased risk of developing the metabolic syndrome and diabetes.

Obesity in type 1 diabetes

People with type 1 diabetes can also develop obesity, and weight gain can be exacerbated by attempts to intensify glucose control with insulin. Such individuals may be more likely to develop vascular complications as a result of the associated metabolic syndrome. It has also been suggested that obesity may result in an earlier onset of type 1 diabetes due to the increased demands on already failing beta-cells in the face of insulin resistance (see the Accelerator hypothesis).

Treatment of Obesity

Treatment of obesity has been convincingly shown to reduce the risk of developing diabetes in those at high risk and can also contribute to improving glucose control and associated metabolic abnormalities in those with established type 2 diabetes. The mainstay is dietary change to reduce energy intake, combined with increased physical activity. Several large studies have shown that such an approach can achieve modest (5-10 %) weight loss which can be largely maintained for up to four years. This is associated with a 50% or more reduction in the risk of progressing from impaired glucose tolerance to diabetes and a number of other health benefits.

In established type 2 diabetes proof of concept studies have shown that the biochemical abnormalities can be effectively reversed with severe energy restriction but most people find it hard to maintain such changes long-term. More modest dietary approaches can help improve glucose control and reduce requirements for medication. Pharmacotherapy can be a useful adjunct to lifestyle change and there is supportive data for the use of orlistat in both diabetes and in pre-diabetes.

Other drugs (topiramate/phentermine combination) and lorcsaserin have been approved in the USA but not in Europe due to concerns over safety. Future drug treatments based on gut hormones with effects on satiety such as long-acting GLP-1 analogues have shown promise in clinical trials but are not yet approved for clinical use in obesity.

Newer approaches to the treatment of diabetes that have a low risk of weight gain or help weight loss such as DPP-IV inhibitors, GLP-1 analogues and renal sodium-glucose co-transporter 2 (SGLT2) inhibitors are being increasingly used, although long-term evidence of superiority in terms of clinical outcomes such as diabetes complications is still awaited.

Bariatric Surgery

Bariatric surgery is being increasingly offered as a treatment for both obesity and diabetes, especially in the more severely obese patients (BMI>35kg/m2). There is no doubt that it is effective for weight loss and it provides proof of concept that weight loss is an effective treatment for type 2 diabetes, as many patients will enter a prolonged period of remission of their diabetes. There remains controversy as to whether improvement in diabetes is due to energy restriction and weight loss or if there are independent glucose-lowering effects as a result of altered gut hormone secretion. The overall risk-benefit compared to conventional therapy seems favourable, but patient selection and careful follow up are important to help achieve the best outcomes.

Prevention of Obesity

From a public health perspective, prevention of obesity is of utmost importance. There is general agreement that the ultimate goal is to promote a healthy diet that is less likely to result in weight gain and to increase physical activity. So far campaigns to encourage individuals to make more appropriate life choices have met with limited or no success, and in some countries legislation is being introduced to limit marketing of the most energy dense foods (such as high sugar soft drinks, and high fat, high sugar snacks) to children and / or to tax such products.

It will also be necessary to work with food producers and marketing experts to reduce sugar and fat content of such foods, promote smaller, more appropriate portion sizes and encourage switching to healthier alternatives – it remains to be seen whether such approaches (such as the ‘responsibility deal’ in the UK) will have a measurable effect

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