- Blood Glucose Abnormalities: The Basics
- Insulin Resistance and HIV
- Causes of Blood Glucose Disorders
- Diagnosis and Monitoring
- Management of Blood Glucose Abnormalities
- Selected Sources
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Metabolic complications associated with HIV disease and its treatment -- including insulin resistance and diabetes, abnormal cholesterol and triglyceride levels (dyslipidemia), and body fat gain or loss -- remain a medical mystery and a topic of intense interest for AIDS researchers and people with HIV alike. While these complications sometimes have been collectively referred to as "lipodystrophy syndrome," it remains unclear whether or how they are related and what causes them (see "HAART Attack: Metabolic Disorders during Long-Term Antiretroviral Therapy," BETA, April 1999).
reverses diabetes type 2 need insulin (☑ carbs allowed per day) | reverses diabetes type 2 blood sugarhow to reverses diabetes type 2 for Scientists are urgently trying to better understand these conditions, which may have a negative impact on quality of life, interfere with adherence to antiretroviral therapy, and lead to long-term health problems. High blood glucose levels (hyperglycemia) and dyslipidemia are a particular concern because in the population at large they have been linked with increased risk of heart disease (see "Cardiovascular Disease the 1 last update 15 Jul 2020 in People With HIV," BETA, Summer/Autumn 2002). Much research is underway and new clues are steadily emerging, but Daniel Kuritzkes, M.D., of Boston''s Hospital predicts, "We''s cells do not respond properly to the hormone and cannot take up glucose, which then builds up in the bloodstream. This causes the beta cells to release extra insulin, leading to high blood insulin levels (hyperinsulinemia). Over time, the beta cells can fail to secrete enough insulin. When the body cannot produce sufficient insulin, or the cells do not respond to it efficiently, the result is hyperglycemia -- impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Eventually, this process can lead to diabetes mellitus (sugar diabetes), a condition characterized by persistent hyperglycemia (see "Progression of Insulin Resistance to Type 2 Diabetes" below).Scientists are urgently trying to better understand these conditions, which may have a negative impact on quality of life, interfere with adherence to antiretroviral therapy, and lead to long-term health problems. High blood glucose levels (hyperglycemia) and dyslipidemia are a particular concern because in the population at large they have been linked with increased risk of heart disease (see "Cardiovascular Disease in People With HIV," BETA, Summer/Autumn 2002). Much research is underway and new clues are steadily emerging, but Daniel Kuritzkes, M.D., of Boston''s Hospital predicts, "We''s cells do not respond properly to the hormone and cannot take up glucose, which then builds up in the bloodstream. This causes the beta cells to release extra insulin, leading to high blood insulin levels (hyperinsulinemia). Over time, the beta cells can fail to secrete enough insulin. When the body cannot produce sufficient insulin, or the cells do not respond to it efficiently, the result is hyperglycemia -- impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Eventually, this process can lead to diabetes mellitus (sugar diabetes), a condition characterized by persistent hyperglycemia (see "Progression of Insulin Resistance to Type 2 Diabetes" below).
There are two primary forms of diabetes mellitus: type 1 and type 2. (Diabetes insipidus is an uncommon condition characterized by excess urine production unrelated to blood sugar abnormalities. Pregnant women may also develop a transient condition known as gestational diabetes. This article is limited to diabetes mellitus).
Type 1 diabetes (also called juvenile onset or insulin-dependent diabetes mellitus [IDDM]) typically occurs at a young age and is believed to result from the destruction of insulin-producing beta cells by the immune system. People with type 1 diabetes produce little or no insulin and usually must receive daily insulin injections.
Type 2 diabetes (also called adult onset, insulin-resistant, or non-insulin-dependent diabetes mellitus [NIDDM]) typically develops later in life -- though it is now being seen in children -- and commonly occurs in people who are overweight. (See "Risk Factors for Blood Glucose Abnormalities" below for more diabetes risk factors.) Type 2 diabetes is a progressive illness that involves a gradual decline in insulin sensitivity and production. It can take years or decades for mild insulin resistance to progress to full-blown diabetes, and many people with impaired insulin sensitivity never develop frank (clinically apparent) diabetes. Those with type 2 diabetes can often be treated with diet modification, increased exercise, weight loss, and/or oral medications, and usually do not require insulin injections. The blood glucose abnormalities that develop in people with HIV resemble type 2, not type 1, diabetes.
Insulin resistance and diabetes are a concern because untreated high blood sugar can lead to a wide range of long-term health problems, including kidney dysfunction, retina damage leading to blindness, nerve damage, erectile dysfunction in men, and pregnancy complications in women. In fact, diabetes is the sixth leading cause of death in the U.S. Yet these complications can occur even in people who never progress from impaired glucose tolerance to frank diabetes.
Hyperglycemia can also contribute to blood vessel abnormalities and cardiovascular disease, including heart attacks and strokes. This process is not well understood -- especially in people with HIV -- but it is thought that excess sugar the 1 last update 15 Jul 2020 in the blood may promote blood clotting and make cholesterol more likely to adhere to blood vessel walls. Both the Caerphilly Heart Study, which followed more than 2,500 men in a Welsh town between 1979 and 1983, and the Prospective Cardiovascular Munster (PROCAM) study, which followed 2,754 men, found that diabetes was associated with about a 2.5-fold increased risk of heart disease.Hyperglycemia can also contribute to blood vessel abnormalities and cardiovascular disease, including heart attacks and strokes. This process is not well understood -- especially in people with HIV -- but it is thought that excess sugar in the blood may promote blood clotting and make cholesterol more likely to adhere to blood vessel walls. Both the Caerphilly Heart Study, which followed more than 2,500 men in a Welsh town between 1979 and 1983, and the Prospective Cardiovascular Munster (PROCAM) study, which followed 2,754 men, found that diabetes was associated with about a 2.5-fold increased risk of heart disease.
Before the availability of highly active antiretroviral therapy (HAART), blood glucose abnormalities were infrequently seen in people with HIV. But in June 1997, soon after protease inhibitors (PIs) came into widespread clinical use, the U.S. Food and Drug Administration (FDA) issued a health advisory warning of an association between PIs and hyperglycemia and diabetes mellitus. Since then, there have been continued reports of insulin resistance in people using anti-HIV therapy.
Different studies have yielded widely varying estimates of the prevalence of impaired glucose metabolism in people on HAART, in part because they have used different tests and inconsistent definitions of the condition. The prevalence of frank diabetes mellitus in people with HIV is relatively low, with studies reporting rates from 0.5% to 15%. But, says Michael Dubé, M.D., of Indiana University School of Medicine, diabetes is "only the tip of the iceberg." Impaired glucose tolerance is considerably more common, affecting an estimated 15-25%, and research suggests that some degree of insulin resistance may occur in one-half of people taking PIs.
reverses diabetes type 2 born (☑ causes) | reverses diabetes type 2 lipidhow to reverses diabetes type 2 for Research also indicates that coinfection with the hepatitis C virus (HCV) -- which affects as many as 40% of people with HIV in the U.S. -- increases the risk of blood glucose abnormalities. Studies have shown that people with chronic hepatitis C are more likely to develop insulin resistance and type 2 diabetes. For example, Shruti Mehta, M.P.H., and colleagues from Johns Hopkins University in Baltimore found that people with HCV were four times more likely to develop type 2 diabetes than HCV negative people; however, they found no association between hepatitis B and diabetes. Mehta''s Interagency HIV Study (WIHS), women receiving PIs were significantly more likely to report that they had diabetes than HIV-negative women (2.8 cases per 100 person-years vs. 1.4 cases per 100 person-years, respectively). Interestingly, in this study HIV-positive women who received no antiretroviral therapy or received only NRTIs were even less likely to report diabetes than HIV-negative women (1.2 cases per 100 person-years).
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It is unclear exactly how PIs affect glucose metabolism, but research points to a variety of possible mechanisms, including reduced glucose uptake by peripheral cells, decreased insulin production by beta cells in the pancreas, and increased glucose production by the liver.
Several laboratory, animal, and clinical studies suggest that PIs may directly interfere with the transport of glucose into cells. An insulin-sensitive protein called Glut-4 plays a key role in transporting glucose into fat and muscle cells after eating. In laboratory studies using 3T3-L1 adipocytes (a type of fat cell), Haruhiko Murata, Ph.D., and colleagues from Washington University in St. Louis found that indinavir and other PIs reduced glucose uptake by inhibiting Glut-4 activity. At 100 micrometers (µm), indinavir reduced glucose uptake by 63%, while a 10 µm dose (closer to the concentrations used in humans) caused a 26% decrease. This inhibition occurred within minutes, and was reversed when indinavir was removed. In another study in frog egg cells, indinavir, amprenavir, and ritonavir (Norvir) reduced glucose uptake by 45%, 42%, and 54%, respectively. Noting that mutant mice lacking Glut-4 have almost no subcutaneous (under the skin) fat, the authors suggested that peripheral lipoatrophy (fat loss in the limbs and face) in people with HIV may be mediated by PIs''s team showing that reduced insulin sensitivity and increased fasting glucose did not trigger beta cells to release more insulin in people taking indinavir.
Proposing yet another mechanism, Dr. Capeau and colleagues found that in laboratory tests, PIs (indinavir, nelfinavir, and amprenavir) inhibit the production and activity of sterol regulatory element binding protein (SREBP), a key fat cell messenger that triggers stem cells to differentiate into adipocytes. SREBP also stimulates increased production of peroxisome proliferating activation factor gamma (PPAR-gamma), which promotes cellular glucose uptake in the presence of insulin.
Marc van der Valk, M.D., from the University of Amsterdam and colleagues reported that in addition to decreased cell sensitivity to insulin, glucose production by the liver is increased in people taking PIs. Using the hyperinsulinemic euglycemic clamp technique (discussed below in the "Diagnosis and Monitoring" section), the researchers found that hepatic glucose production was 47% higher in the PI recipients than in HIV-negative control subjects. In addition, insulin suppressed glucose production less in the PI group than in controls. Similarly, Dr. Noor''s Hospital in Sydney found that among people taking PIs, insulin resistance was more common in those with body shape changes -- either abdominal obesity or peripheral fat loss. Dr. Carr''s team found that insulin levels were most elevated in HIV-positive women with abdominal fat accumulation, independent of PI use. The same research group also reported insulin resistance in men with AIDS-related wasting syndrome who were treated with NRTIs but not PIs, and noted that reduced lean body mass and increased abdominal fat were the primary predictors of hyperinsulinemia. In addition, they found that when 52 HIV-positive hypogonadal (low testosterone level) men with AIDS-related wasting were given supplemental testosterone therapy, their insulin sensitivity improved as their lean body mass increased. (It should be noted, however, that supplemental testosterone may provide no additional benefit in men who already have normal levels.)
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Some research suggests that the relationship between body fat changes and glucose abnormalities may be mediated by free fatty acids. Normally, fatty acids are released when blood sugar levels are low to provide the liver with "raw material" for gluconeogenesis. High blood levels of free fatty acids -- related to both visceral fat accumulation and peripheral fat loss -- may interfere with normal glucose regulation and are associated with greater insulin resistance.
Dr. Hadigan''s team reported that glucose disposal was reduced in people with elevated lactic acid levels, a possible indication of NRTI-induced damage to the mitochondria, energy-producing organelles in cells that are involved in glucose metabolism.
Interestingly, research has not implicated non-nucleoside reverse transcriptase inhibitors (NNRTIs) in blood glucose abnormalities, although they have been linked with other metabolic manifestations in some studies.
Yet other data indicate that blood glucose abnormalities are not directly caused by body fat changes or dyslipidemia. Dr. Mulligan and colleagues, for example, found that blood glucose abnormalities developed just a few months after people began taking PIs, well before body shape changes occurred. Dr. Saint-Marc''s syndrome, characterized by many of the same symptoms. However, more recent research has shown that cortisol levels generally are not elevated in HIV-positive people with metabolic complications.
Glucose abnormalities may also be associated with altered levels of cytokines (chemical messengers produced by cells), including tumor necrosis factor (TNF). An increased number of TNF receptors (cell proteins that bind to TNF) is an indication of inflammation, or immune activation, which can potentially occur as HAART enables immune system recovery. Research by Dr. Mynarcik and others has shown that elevated TNF receptor levels are associated with both insulin resistance and lipoatrophy. Donald Kotler, M.D., of St. Luke''s team in HIV-positive people with lipodystrophy, have shown that dietary fiber promotes insulin sensitivity and helps maintain normal glucose levels. Moreover, research suggests that reducing calories can improve insulin sensitivity even before weight loss occurs. In HIV-positive people who have problems with wasting, however, a low-calorie diet may not be appropriate.
When it comes to nutrition and HIV, more is not necessarily better. Sounding a note of caution, Grace McComsey, M.D., and colleagues from Case Western Reserve University in Cleveland reported recently that in ten HIV-positive, NRTI-treated individuals with lipoatrophy or lactic acidosis, administration of antioxidants (vitamin C, vitamin E, and N-acetyl cysteine) led to worsened insulin resistance and significantly elevated fasting glucose levels. These results are interesting because some past research has suggested that antioxidants may improve insulin sensitivity. Given the current climate of uncertainty, people with HIV should consult a physician -- and ideally an HIV-knowledgeable dietitian -- before making any major dietary changes.
Antiretroviral Selection and Substitution
Concern about blood glucose abnormalities and other metabolic complications has contributed to changes in how clinicians approach antiretroviral therapy. For example, it is now recommended that treatment be delayed in asymptomatic individuals until the CD4 cell count falls below 350 cells/mm3 or viral load rises above 55,000 copies/mL. In addition, according to the IAS guidelines, it is reasonable to consider avoiding lipid-elevating PIs (especially as first-line therapy) in people with pre-existing glucose metabolism abnormalities or risk factors for diabetes.
For those who have already started therapy, several studies have shown that switching from PIs to antiretroviral drugs from other classes can help normalize blood glucose levels and prevent progression from insulin resistance to frank diabetes. For example, Esteban Martinez, M.D., of University Hospital Clinic in Barcelona and colleagues demonstrated in two separate studies that switching from PIs to nevirapine (Viramune) or efavirenz (Sustiva) significantly improved insulin sensitivity. Similarly, Dr. Walli''s team found that metformin improved fasting insulin levels, decreased triglyceride levels, and reduced visceral fat. However, Dr. Martinez and colleagues reported that in their study, metformin had only a minimal effect on insulin resistance, abdominal fat, and blood lipid levels.
Thiazolidinedione drugs improve insulin sensitivity. They work by activating PPAR-gamma, a cytokine that promotes the production of adipocytes and stimulates cells to take up more glucose. As with the biguanides, some studies show that the thiazolidinediones may help improve body fat distribution and normalize blood lipid levels.
In a study by Jussi Sutinen, M.D., and colleagues from Helsinki University Central Hospital, 30 HIV-positive subjects with lipodystrophy received either rosiglitazone or a placebo. After 24 weeks, insulin levels decreased in the rosiglitazone group but not in the placebo arm. However, triglyceride and cholesterol levels rose among those taking rosiglitazone, and there was no effect on visceral or subcutaneous fat distribution. "Rosiglitazone seemed to ameliorate insulin resistance judged by the decreased serum insulin concentrations and percentage of liver fat," the authors concluded.
Marie Gelato, M.D., and colleagues from the State University of New York at Stony Brook found that in eight HIV-positive individuals treated with rosiglitazone for 6-12 weeks, insulin resistance improved, as it did in Dr. Sutinen''s team also found that rosiglitazone was associated with improved insulin sensitivity and increased subcutaneous fat in a study of 28 HIV-positive participants, but in that study total and LDL cholesterol levels rose in the treatment arm.
Most physicians do not routinely recommend the older sulfonylurea drugs (which work by increasing insulin secretion by beta cells) for people with impaired glucose metabolism associated with antiretroviral therapy. These drugs do not directly improve insulin sensitivity and may worsen hyperinsulinemia.
Because the various antidiabetic drugs work by different mechanisms, a combination approach may be beneficial. The AIDS Clinical Trials Group is currently recruiting participants for ACTG 5082, a randomized study comparing metformin plus rosiglitazone with metformin alone or rosiglitazone alone in HIV-positive people with insulin resistance and lipodystrophy (see "Open Clinical Trails" for details).
Drug Interactions and Contraindications
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The most common side effects of metformin are nausea and diarrhea (especially when the drug is first started), which could be a problem if the drug is used with antiretroviral drugs that cause similar symptoms. And, because metformin has been shown to cause weight loss, it may be a poor choice for HIV-positive people with severe wasting. Conversely, for others it might be advantageous that the drug does not cause weight gain.
The thiazolidinediones can cause liver toxicity, and should be used with extreme caution and careful monitoring in people with signs of liver damage or pre-existing liver disease, including chronic hepatitis B or C. They may also present a problem for people taking antiretroviral drugs that are metabolized by the liver and are themselves associated with liver toxicity. One drug in this class, troglitazone (Rezulin), was taken off the market in 2000 after being linked to fatal liver failure. But rosiglitazone, a newer agent, appears to have less impact on the liver and fewer interactions with PIs. In a further note of caution, researchers reported in the September 9, 2003 issue of the Mayo Clinic Proceedings that rosiglitazone and pioglitazone (Actos) were associated with fluid buildup in the lungs and heart failure in six HIV-negative men with pre-existing heart and kidney dysfunction.
Because blood glucose abnormalities and other metabolic complications often occur together in people with HIV, it is important to be aware of potential interactions between antidiabetic medications and drugs used to treat other, possibly related, conditions. For example, some research has shown that niacin (Niaspan), which is used to lower blood lipid levels, may worsen insulin resistance. People with HIV should inform their physicians and other health-care providers about all therapies they are taking, including prescription and over-the-counter medications, herbal remedies, nutritional supplements, and recreational drugs.
The understanding of insulin resistance, diabetes, and other metabolic complications in people with HIV has evolved rapidly in recent years, but much remains to be learned. While the exact causes of blood glucose abnormalities are not yet known, several contributing factors -- including protease inhibitors and body fat changes -- have been implicated.
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By working with their healthcare providers to maintain a healthy blood sugar level, people with HIV can potentially prevent the development of serious long-term complications such as diabetes and cardiovascular disease.
Liz Highleyman ([email protected]) is a freelance medical writer and editor based in San Francisco.
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Mehta, S. and others. The for 1 last update 15 Jul 2020 effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons. Journal of Acquired Immune Deficiency Syndromes 33(5): 577-584. August 15, 2003.Mehta, S. and others. The effect of HAART and HCV infection on the development of hyperglycemia among HIV-infected persons. Journal of Acquired Immune Deficiency Syndromes 33(5): 577-584. August 15, 2003.
Mulligan, K. and others. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. Journal of Acquired Immune Deficiency Syndromes 23(1): 35-43. January 1, 2000.
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Noor, M. and others. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 15(7): F11-8. May 4, 2001.
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Schambelan, M. and others. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. Journal of Acquired Immune Deficiency Syndromes 31(3): 257-275. November 1, 2002.
Sutinen, J. and others. Rosiglitazone in the treatment of HAART-associated lipodystrophy: a randomized double-blind placebo-controlled study. Antiviral Therapy 8(3): 199-207. June 2003.
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