Diabetes is a disease where the body does not produce enough, or dose not respond to the hormone insulin. This affects the regulation of the amount of glucose in the blood.

There are two main type of diabetes:

• Type I diabetes is caused by the body not producing enough insulin. This prevents the body's cells from using glucose properly. Type I diabetes is often diagnosed in childhood, and was previously known as 'juvenile diabetes'.

• Type II diabetes is caused by the body failing to respond to insulin. This is termed 'insulin resistance' and is more common than type I diabetes. Type II diabetes can be caused by obesity and lack of exercise, and usually develops with age. It is a common side-effect of some antiretroviral drugs.

Type II diabetes in HIV disease

The development of type II diabetes has been reported in 2 to 10% of people taking anti-HIV therapy, with prevalence growing as time on therapy increases. At least three cases of type II diabetes in African men with advanced HIV infection have also been reported. Since these resolved with antiretroviral therapy, it is possible that this disease could also be linked to HIV itself^[1][2].

Type II diabetes is the form of diabetes that develops in adults as a result of a gradual decline in insulin sensitivity and a decline in insulin production. Insulin is the hormone that regulates levels of glucose in the blood and uptake of glucose into various tissues. Glucose is needed by cells for energy. Over time, cells may be less able to take up the glucose that builds up in the bloodstream after a meal. When this happens, people are said to be insulin resistant, which means that they require more insulin to maintain glucose levels within a normal range. As insulin resistance increases, fat cells release fatty acids in a bid to supply the liver with more raw materials to make glucose, but this fails to restore normal levels of glucose.

Eventually, glucose levels will rise to a point where physical symptoms of hyperglycemia (high blood sugar) occur. These include:

• Fatigue.

• Frequent urination, due to the need to get rid of excess glucose.

• Constant thirst due to loss of fluid.

• Blurred vision.

• Weight loss.

More serious problems can emerge in cases of severe type II diabetes, such as

• Lesions in the retina of the eye.

• Kidney disorders (diabetic nephropathy).

• Nerve damage, especially in the legs (diabetic neuropathy).

• Impotence.

• Bacterial or fungal skin infections.

• Cardiovascular disease (angina, stroke, heart attack).

Diabetes substantially increases the risk of heart disease, in part because when large amounts of glucose are present in the blood, the sugar becomes attached to low-density lipoprotein (LDL) or 'bad' cholesterol. This causes the cholesterol to be oxidised more easily and thus taken up into the wall of blood vessels where it forms plaques that contribute to hardening of the artery and eventual heart disease. When sugar attaches to high density lipoprotein (HDL) or 'good cholesterol, it is less easy for this cholesterol to be removed from the bloodstream by the liver. High glucose levels also increase blood clotting and reduce the flexibility of blood vessels, both contributory factors in the development of cardiovascular problems.

See Metabolic changes on antiretroviral therapy in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for further discussion of the incidence of diabetes among people on antiretroviral therapy.

Unlike other aspects of the metabolic and body fat changes that occur in people taking HAART, there is clear experimental evidence that in people with HIV, insulin resistance is caused by certain drugs, particularly indinavir (Crixivan). Switching therapy can reduce glucose levels. As a class, the protease inhibitors have been associated with diabetes and impaired sugar metabolism.

An analysis of the prevalence and incidence of blood glucose abnormalities in men enrolled in the Multicenter AIDS Cohort Study (MACS), found that the risk of prevalent and incident fasting hyperglycaemia was two to three times greater, and the risk of diabetes was four to five times greater in HIV-positive men on HAART compared with HIV-negative men. Use of antiretroviral therapy was associated with a significantly increased risk of hyperglycaemia, but other factors, including HIV disease severity and CD4 cell count may also play an important role (Brown 2004).

Coinfection with hepatitis C appears to further increase the risk of diabetes and hyperglycaemia in HIV-positive people, according to data from the United States Department of Veterans' Affairs and the team at John Hopkins University (Butt 2003; Mehta 2003). Hepatitis C co-infection may be especially important in patients over 40 years of age, as may a history of acute pancreatitis (Crane 2004).

Obesity is a major factor in developing type II diabetes in non HIV-infected individuals. A recent study found that obesity is becoming an increasingly important complication of HIV disease, with women and African Americans more likely to suffer from both. The risk also increased for everyone as CD4 cell counts increased, and, ironically, was reduced by smoking, which is itself a major risk factor for cardiovascular disease (Amorosa 2004).

See Treating body fat and metabolic changes - switching drugs in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for discussion of these studies.

Treatment of type II diabetes

In people receiving HAART, regular monitoring of glucose levels should take place, so that steps can be taken to reduce rising glucose levels before diabetes develops. However, type II diabetes may emerge very rapidly after beginning a new drug combination, and it is not unknown for individuals to go from slightly elevated glucose levels to a diabetic state in a matter of weeks.

Central obesity is known to predispose people to the development of type II diabetes, because the fat around the organs is highly insulin resistant.

The first step in normalising glucose levels is to increase exercise levels, so that the heart rate rises above normal levels for at least 20 minutes each day. Brisk walking may be enough to achieve this. Swimming, cycling, jogging or more structured exercise such as aerobics classes are also good.

Diet

Dietary changes recommended for people with diabetes include:

• Increasing fibre by eating more wholegrains, beans, and fresh fruit and vegetables.

• Reducing consumption of saturated fats (i.e. animal fats such as butter, lard, cream).

• Reducing consumption of trans fatty acids (margarine) and hydrogenated fats (found in prepared foods, e.g. cakes, biscuits, pizza).

• Increasing consumption of polyunsaturated fats (oils from corn, sunflower, safflower, and soybeans).

Consultation with a specialist HIV dietitian is recommended before commencing a diet targeting diabetes, to ensure it will not worsen wasting, levels of blood fats, or the absorption of anti-HIV drugs.

The extent to which dietary changes can improve insulin resistance and diabetes in people with HIV has not been established. Case studies suggest that some individuals see an improvement after dietary intervention but some trials have reported disappointing results. These studies are discussed in detail in Treating body fat and metabolic changes in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment.

If diet and exercise changes are not enough to normalise glucose levels, and antiretroviral drugs cannot be switched to remove the agent that is causing the glucose elevation, drug therapy for diabetes may be recommended. Patients starting diabetes drugs should continue to exercise and persist with changes to diet, to help to lower blood sugar.

Drug treatment for type II diabetes

Drug therapy for diabetes aims to reduce fasting glucose levels and a marker called glycosylated haemoglobin (HbA_1c), which is formed from the oxygen-carrying blood protein with glucose attached. As glucose levels in the blood rise, so does the amount of glycosylated haemoglobin.

Therapy also aims to lower the peak in glucose levels after food, since a rise in glucose levels after eating plays an important role in stimulating insulin resistance and in the development of the complications of diabetes such as retinal damage, neuropathy and kidney damage.

The first line of treatment, usually adopted in less severe cases, is to use the class of antihyperglycemic drugs called sulphonylureas. These include glipizide (Glibenese), and glimepiride (Amaryl). These drugs stimulate the pancreas, a small organ located near to the liver in the centre of the abdomen, to produce more insulin. The drawback of this class of drugs is that they can cause weight gain of up to 5kg. Also, sulphonylureas can cause blood sugar to fall too low, leading to the state called hypoglycaemia.

Glyburide is not recommended for use in people with renal insufficiency (reduced ability of the kidneys to remove waste products), and is also associated with a higher risk of hypoglycaemia. Glipizide and glimepiride are less likely to cause weight gain

An alternative first-line treatment is metformin (Glucophage), which does not act directly on insulin, but instead reduces production of glucose in the liver. Metformin tends to reduce weight, unlike the sulphonylureas, and has a comparable effect on HbA, as well as reducing insulin levels. It is therefore used commonly in obese patients, but is not suitable for people with antiretroviral-induced fat loss.

Metformin may also reduce triglyceride and LDL cholesterol levels, both of which are often elevated in people with high glucose levels on HAART. Long-term metformin treatment is also associated with a lower risk of heart attack when compared to dietary adjustment or sulphonylurea. One study has shown that a combination of metformin and exercise helps to reduce the risk of heart disease and improves body fat redistribution in HAART-treated HIV-positive patients (Driscoll 2004).

The most frequent adverse effects of metformin treatment are abdominal pain, nausea and diarrhoea, which have been reported by up to 50% of patients during the first few weeks of treatment. This side effect profile may make metformin difficult to tolerate for people who are taking protease inhibitor-containing regimens. However, diarrhoea and gastrointestinal problems are less frequent if metformin is taken with food.

Metformin may also increase the risk of lactic acidosis in people taking nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is important that gastrointestinal symptoms of lactic acidosis are not dismissed as known side effects of metformin.

The third class of drugs is the thiazolidinediones, often referred to as glitazones. These drugs increase insulin-stimulated uptake of glucose by muscle cells, but may have other modes of action that are still unclear. This class includes rosiglitazone (Avandia) and pioglitazone (Actos), and has shown equivalent effects to metformin and the sulphonylureas in the control of insulin. In addition, the drugs have also been shown to improve HDL cholesterol levels and reduce triglyceride levels, reduce blood pressure and clotting, but no long-term studies have yet reported on their impact on the risk of cardiovascular disease.

Glitazones are also associated with weight gain, but this effect may not be entirely unwelcome in people with lipodystrophy, because glitazones have been shown to reduce visceral fat deposits and increase levels of subcutaneous fat. However, there is conflicting evidence about this effect on fat distribution in HIV-related lipodystrophy. Two randomised studies in people with varying glucose levels and HAART-associated lipoatrophy showed no improvement in subcutaneous fat levels or weight (Sutinen 2003; Carr 2004). However, another randomised study of HIV-positive patients with drug-induced insulin resistance found that subcutaneous fat increased over three months in the patients treated with rosiglitazone compared with negligible change in people on placebo, coupled with improvements in insulin resistance (Hadigan 2004). The reason for these different findings is not understood. It is possible that subcutaneous fat may not increase if underlying adipose cells have been lost. Alternatively, peripheral fat gain may only be expected when there is an minimum level of insulin and glucose disturbance to correct.

A concern with the use of rosiglitazone in HIV patients is the finding that it boosts blood levels of triglycerides and cholesterol (Sutinen 2003; Hadigan 2003). Elevated lipids are a known risk factor for heart disease and stroke, but the specific long-term consequences of glitazone treatment in the HIV-infected patients who are taking antiretroviral are unknown. There has also been a report of the development of lipomas, small, benign tumours of fat cells, in an HIV-positive man taking the drug (Mafong 2004).

See Treating body fat and metabolic changes - switching drugs in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for further information on use of this class of drugs in the treatment of lipodystrophy.

Therapy may also include the use of insulin in the form of an injection, or a combination of oral agents to achieve control of glucose levels. For example, metformin is available as a co-formulation with glyburide and may be suitable for use in cases where people are unwilling to inject insulin each day. Insulin therapy is usually reserved for severe cases of type II diabetes, although some experts believe that if it could be used earlier, remission of type II diabetes might be achieved more frequently.

References

Amorosa V et al. A Tale of 2 Epidemics: The Intersection between Obesity and HIV Infection in the Urban United States. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 879, 2004.

Brown T et al. Prevalence and incidence of pre-diabetes and diabetes in the Multicenter AIDS Cohort Study. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 73, 2004.

Butt AA et al. Understanding the association between DM and HIV and HCV infections in the era of HAART. Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-1715, 2003.

Carr A et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet 363: 429-438, 2004.

Crane H et al. History of Acute Pancreatitis and Hepatitis C Virus Infection Increase the Risk of New-onset Diabetes among HIV-infected Patients. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 878, 2004.

Driscoll SD et al. Effects of exercise training and metformin on body composition and cardiovascular indices in HIV-infected patients. AIDS 18: 465-473, 2004.

Hadigan C et al. Effects of rosiglitazone on metabolic indices and fat in HIV lipodystrophy: a randomized controlled trial. Ann Intern Med 140: 786-794, 2004.

Mafong DD et al. Development of multiple lipomas during treatment with rosiglitazone in a patient with HIV-associated lipoatrophy. AIDS 18: 1742-1744, 2004.

Mehta SH et al. The effect of HAART on HCV infection on the development of hyperglycemia among HIV-infected persons. Journal of Acquired Immune Deficiency Syndromes 33: 577-584, 2003.

Nathan DM et al. Initial management of glycemia in type 2 diabetes mellitus. New England Journal of Medicine 347 (17): 1342-1349, 2002.

Sutinen J et al. Rosiglitazone in the treatment of HAART-associated lipodystrophy--a randomized double-blind placebo-controlled study. Antiviral Therapy 8(3): 199-207, 2003.