Apparent Resolution of Type 2 Diabetes Mellitus after Initiation of Potent Antiretroviral Therapy in a Man from Africa with HIV Infection
- 1Divisions of Infectious Diseases, University of Colorado at Denver Health Sciences Center, Denver
- 2Divisions of Endocrinology, Department of Medicine, University of Colorado at Denver Health Sciences Center, Denver
- Reprints or correspondence: Dr. John Koeppe, Dept. of Medicine, Div. of Infectious Diseases, University of Colorado at Denver Health Sciences Center, 4200 E. Ninth Ave., B-163, Denver, CO 80262 (John.Koeppe{at}uchsc.edu).
Abstract
We describe a 52-year-old African man with human immunodeficiency virus infection and type 2 diabetes mellitus whose diabetes resolved as viral replication was suppressed with protease inhibitor—based antiretroviral therapy. This case suggests that human immunodeficiency virus infection itself can precipitate overt diabetes mellitus.
In the era of HAART, a number of metabolic problems have emerged among the HIV-infected population, including lipodystrophy, dyslipidemia, and insulin resistance [1, 2]. It is likely that antiretroviral therapy plays a major role in these disorders [2–7]. However, HIV infection itself has been associated with metabolic disturbances. In the pre-HAART era, advanced HIV infection with wasting was associated with hypertriglyceridemia and low levels of high-density lipoprotein cholesterol and low-density lipoprotein cholesterol [8, 9].
There are few data on insulin sensitivity among the HIV-infected population in the pre-HAART era. One study found that insulin sensitivity actually increased in men with HIV infection, compared with healthy control subjects [10]. In another study, women with HIV infection had higher insulin levels than healthy control subjects, suggesting increased insulin resistance among the female, HIV-infected population [11]. Finally, a third study found that a small number of therapy-naive patients with HIV infection had normal insulin sensitivity [3]. In our case report, we describe a patient whose diabetes mellitus and HIV infection were diagnosed concurrently and whose diabetes resolved upon suppression of HIV-1 replication. This is, to our knowledge, the third case report that strongly suggests HIV infection itself can precipitate diabetes mellitus [12].
Case report. The patient was a 52-year-old African man who presented to a clinic in Nairobi, Kenya, in October 2003 with an 18-kg weight loss; at that time, he was diagnosed with HIV infection and diabetes mellitus. He moved to the United States and was seen 1 month later in Minnesota with complaints of polyuria and polydipsia. Treatment with metformin (1000 mg each morning and 500 mg each evening) was begun. He received no further care in Minnesota, and 4 months later he came to our clinic in Devner, Colorado, with ongoing complaints of polyuria and polydipsia, as well as blurred vision and fatigue. The findings of an examination of his systems were otherwise normal, and he was taking the previously prescribed metformin.
His past medical and surgical history were significant for only 2 episodes of malaria treated with chloroquine >10 years before. There was no family history of diabetes, and the patient did not smoke or use alcohol or drugs.
On physical examination, his weight was 66.8 kg, and his height was 183 cm (body mass index, 19.9). His systolic/diastolic blood pressure was 100/61 mm Hg, and his heart rate was 65 beats per min. He was afebrile with a normal respiratory rate. Findings of a physical examination were normal, except for a generally cachetic appearance with temporal wasting. There was no evidence of retinopathy or neuropathy.
Laboratory studies performed during the next 2 weeks revealed a CD4+ cell count of 84 cells/µL (14% lymphocytes), an HIV-1 load of 3,935,792 copies/mL, a random glucose level of 409 mg/dL, a fasting glucose level of 249 mg/dL, and a hemoglobin A1c level >14.5%. Islet cell antibodies were negative, and c-peptide levels were in the normal range at 1.5 ng/mL. Creatinine, anion gap, and hematocrit levels and liver function test findings were all normal, and the patient's hepatitis B virus and hepatitis C virus test results were negative.
The metformin dosage was increased to 1000 mg twice per day; glyburide was started at 5 mg each morning and was increased to 10 mg each day during the following few weeks. The patient did not want to participate in home glucose monitoring but did agree to come in for periodic random glucose level testing. Within ∼1 week of starting glyburide, he also started daily trimethoprim-sulfamethoxazole prophylaxis and enrolled in the AIDS Clinical Trial Group (study number A5073), for which he received emtricitabine (200 mg daily), tenofovir (300 mg daily) and lopinavir-ritonavir (six 133.3-mg/33.3-mg capsules daily).
Approximately 1 month after starting potent antiretroviral therapy, the patient reported symptoms of hypoglycemia, and the glyburide dose was decreased. Two months into his antiretroviral therapy regimen, the patient's CD4+ count increased to 254 cells/µL (14%), and his viral load decreased to 3320 copies/mL. At the same time, his fasting glucose level was 44 mg/dL, and his Hgb A1c was 7.1%. A few months later, he stopped both the glyburide and metformin, and 6 weeks later his Hgb A1c was 5.8%, with a normal hematocrit. During this time, he gained ∼9 kg (body mass index, 22.6) without any evidence of central fat accumulation.
Three months later, his treatment was complicated by the development of ruptured appendicitis that ultimately led to a sepsis-like syndrome with multiple-organ failure requiring hemodialysis. During this time, antiretroviral therapy was stopped. During hospitalization, he required sliding-scale insulin, and his Hgb A1c increased to 7.1%. After resolution of multiple-organ failure and recovery of normal renal function, he did not require therapy for diabetes. Most recently, 7 weeks after his last hospitalization and 2 weeks after restarting HAART with abacavir-lamivudine (one 600-mg/300-mg daily) and lopinavir-ritonavir (six 133.3-mg/33.3-mg capsules daily), his Hgb A1c was 5.4%. His hematocrit on this day was 36.8% but has since normalized. His most recent plasma glucose level, measured 8 months after hospital discharge, was 72 mg/dL.
Discussion. In this era of potent antiretroviral therapy, insulin resistance is frequently found in patients with HIV infection. Protease inhibitor therapy in particular has been linked to changes in insulin sensitivity. In clinical studies, this has been primarily manifested as decreased insulin-stimulated glucose uptake [6, 14], decreased glucose tolerance [5], and impaired metabolism of free fatty acids and very low-density lipoprotein [5]. In vitro data suggest that the protease inhibitors may cause insulin resistance by inhibiting the transport function of the insulin-regulated glucose transporter isoform Glut4 [22].
Among the HIV-infected population, lipodystrophy is also associated with insulin resistance. HIV lipodystrophy is characterized by loss of subcutaneous fat and by preservation or increases in visceral fat, and these body composition changes are independently associated with insulin resistance in individuals with HIV infection [15]. Recent data also suggest that low levels of adiponectin may play a role in the insulin resistance associated with HIV lipodystrophy [16].
Our case suggests that HIV infection itself may precipitate type 2 diabetes mellitus and that effective viral suppression can reverse this disorder. In 2 other cases, treatment of advanced HIV infection was also associated with apparent resolution of apparent type 2 diabetes mellitus [12]. Interestingly, the men with these cases were also of African descent. One was also treated with a protease inhibitor—based regimen, and the other received a nonnucleoside reverse-transcriptase inhibitor—based regimen. In all 3 of these cases, resolution of diabetes coincided with effective therapy for HIV infection. This suggests that uncontrolled viral replication can directly or indirectly cause insulin resistance and, perhaps, β-cell dysfunction.
Opportunistic infections have also been associated with the onset of diabetes. For example, opportunistic cytomegalovirus infection has been associated with the onset of diabetes that resolved with effective gancyclovir therapy [13]. In our patient, there was no clinical evidence of an opportunistic infection, and he did not have any symptoms of an immune reconstitution syndrome after starting HAART. Therefore, we think that this is an unlikely explanation for the onset and resolution of his diabetes.
How HIV infection itself can cause insulin resistance and/or β-cell dysfunction and, therefore, diabetes mellitus is not entirely clear. Advanced HIV disease may be associated with increases in counterregulatory hormones. Mild basal hypercortisolism has frequently been described in patients with HIV infection, and it is possible that as HIV disease progresses, a further stress response may ensue [17]. Growth hormone is another counterregulatory hormone, but HIV infection is associated with reductions in growth hormone action, which is evidenced by decreased circulating levels of insulin-like growth factor—1 [21]. There is little information about epinephrine and glucagon levels in HIV infection.
Alterations in cytokine levels could also play a role in insulin resistance associated with HIV infection. In 1 study, there was a linear correlation between serum TNF-α levels and insulin resistance in individuals with HIV infection who were experiencing dual nucleoside therapy failure. However, in this same study, healthy control subjects had levels of both TNF-α and IL-1β similar to those of the HIV-infected patients [18]. In another study, higher levels of TNF-α and TNF receptors I and II were found in individuals with HIV infection who had lipodystrophy, compared with control subjects with only HIV infection. However, the levels of TNF receptors I and II decreased significantly after stopping protease inhibitor therapy, suggesting these elevated levels were related to the medications and not to HIV infection, per se [19]. Recently, IL-6 has been shown to correlate with markers of insulin resistance [23].
HIV infection itself may directly alter glucose metabolism. The HIV protein vpr has been shown to act as a glucocorticoid agonist [20], and more recently, vpr was shown in vitro to block the transport of the foxo3a protein from the nucleus to the cytoplasm [24]. The foxo3a protein promotes gluconeogenesis when located in the nucleus, and this effect stops when the protein translocates to the cytoplasm. The vpr protein may, therefore, upregulate gluconeogensis in HIV-positive individuals.
On the basis of the available literature, it would appear that the type 2 diabetes in our patient and in 2 similar cases may represent an unusual complication of HIV infection. The cause of insulin resistance and/or β-cell dysfunction in these instances is not clear; however, a genetic predisposition may be important. In summary, we have presented another case of diabetes in an HIV-infected individual that resolved with effective antiretroviral therapy. This case highlights the complicated changes in glucose metabolism that can occur because of HIV infection and antiretroviral therapy.
Acknowledgments
Potential conflicts of interest. J.K. and L.K.: no conflicts.
- Received December 15, 2005.
- Accepted January 24, 2006.
- © 2006 by the Infectious Diseases Society of America
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