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Insulin Resistance/Diabetes and HIV and Hepatitis C; Aging/HIV & diabetes
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Judith A. Aberg, M.D.
NYU/Bellevue ACTU, Director of HIV Services-Bellevue
Contribution by Jules Levin: Hepatitis C and Insulin Resistance/Diabetes
TOPICS
--What is Insulin Resistance and Diabetes & Why is it Important?
--HIV+ Men Were 3 Times More Likely to Have Diabetes than HIV- Men in MACS
--HIV+ Women: risk for developing diabetes is associated--over 50 yrs of age, smoking cigarettes, being Hispanic, body mass index (weight)
--Reyataz: did not impair sugar metabolism & raise triglycerides in healthy volunteers
--Comparative Effects of Nelfinavir & Efavirenz on Lipids & Glucose in ACTG 384 Study
--Lipids & Sugar Metabolism Improve in NEFA Study After Switch from Protease Inhibitor to Nevirapine, Efavirenz or Abacavir Regimens
--Aging & HIV: diabetes found to be associated with cognitive impairment in older HIV+ individuals; perhaps, a new risk factor for older HIV+ individuals
SUMMARY notes by Jules Levin:
This articles reports on studies presented at the 11th Retrovirus Conference (February 2004) and highlights the concern that persons with HIV can be at greater risk for developing diabetes. This report also highlights research findings that diabetes may be more prevalent in older HIV+ individuals and may lead to cognitive impairment, this identifying a new risk factor associated with aging with HIV.
One study at CROI, the MACS study, looked at 1000 men, and found HIV-positive men were 3 times more likely than HIV-negative men to develop diabetes, and taking HAART appeared to increase the risk. Another study presented at the conference found Reyataz did not lead to elevations in glucose (sugar) in the body in healthy volunteers. Researchers from Bristol Myers Squibb gave healthy volunteers either Kaletra or Reyataz. Study subjects receiving Kaletra were 25-35% less able to process sugar/glucose compared to study subjects receiving Reyataz or placebo. Study subjects receiving Reyataz were not impaired in processing sugar/glucose. As well, study subjects receiving Kaletra had a 43% increase in triglycerides but healthy volunteers receiving Reyataz had no increase in triglycerides. These study results confirm what has already been observed in studies in vitro (test tube) and in HIV+ individuals.
Dr Aberg reports below the results of a substudy from ACTG 384 looking at lipids in patients taking nelfinavir or efavirenz and d4T/ddI or AZT/3TC. For the most part d4T/ddI is not recommended to be used anymore due to side effects and toxicities. Overall, the protease inhibitor nelfinavir and the NNRTI efavirenz appear to have comparable effects on fasting lipids, with a better total:HDL-C ratio with EFV. HDL-C is thgood cholesterol and the total:HDL-C ratio is considered to reflect risk for heart disease, so a better ratio suggests less risk for heart disease. Lipids tended to be slightly more favorable with ZDV+3TC than ddI+d4T. Insulin resistance worsened for all patients regardless of which study drugs they received, but did not differ between regimens.
The lack of an early increase in insulin resistance with nelfinavir suggests that acute insulin resistance is not a PI drug class effect. And of course the results from studies of Reyataz confirm this.
The future: HIV & Aging: new risk factors in HIV? Dr Aberg reviews below a study examining aging and the impact of metabolic abnormalities. The impact on aging and its association with development of dementia in HIV is unknown. The investigators took a step further and asked whether the metabolic complications associated with HIV have even more of an impact on the aging HIV-infected population. The study found that 15% of HIV+ individuals >50 years of age had diabetes; and cognitive impairment was associated with having diabetes. See details of this interesting study below. Increased research efforts on HIV & aging is likely to be and should be emphasized in the future as we all get older with HIV.
What is Insulin Resistance and Diabetes & Why is it Important?
There were several interesting abstracts presented at CROI suggesting that insulin resistance and diabetes are associated with HIV and/or its therapies, particularly some of the protease inhibitors. But first, I think it would be beneficial to just briefly discuss what insulin resistance is and why one should be concerned about developing it. When one consumes carbohydrates, the body breaks it down into sugars, also called glucose. The body also produces insulin which carries the sugar out of the bloodstream and into the tissue and cells. The body does this so that it tries to maintain our blood sugar in what we label as a normal range of blood sugar. Some people require higher amounts of insulin to maintain glucose in a normal range and this is called insulin resistance. Insulin resistance by itself is associated with vascular disease and over time may progress to diabetes where the body no longer can keep the blood sugar in the normal range. Mild diabetes can sometimes be managed by diet and exercise but frequently patients need to take pills or even shots of insulin to control the blood sugar. Uncontrolled diabetes may lead to kidney disease, blindness, neuropathies, vascular disease and even death. But even insulin resistance without diabetes can have major unhealthy effects including elevated blood pressure, abnormal lipids and coronary heart disease which also can lead to significant illness and death.
HIV+ Men Were 3 Times More Likely to Have Diabetes than HIV- Men in MACS
Brown and colleagues presented abstract #73, Prevalence and Incidence of Pre-diabetes and Diabetes (DM) in the Multicenter AIDS Cohort Study. They examined the prevalence of hyperglycemia (elevated blood glucose) in 1107 men enrolled in the Multicenter AIDS Cohort Study, using data from April 1999 through September 2002.
Hyperglycemia (pre-diabetes and DM) was defined as a fasting plasma glucose (FPG) >110 mg/dL, use of anti-diabetic medication, or self-reported diagnosis of DM. DM was defined as a FPG >126 mg/dL, use of anti-diabetic medication, or self-reported diagnosis of DM. Of the 1107 men, 563 were HIV- and 544 were HIV+ (423 on HAART).
Of HIV+ men on HAART, 14% had prevalent DM at baseline compared with 5% in the HIV- group (odds ratio = 4.4; 95% confidence interval [CI]: 2.6, 7.4, after adjustment for age and body mass index [BMI]). For the 618 men with a FPG (fasting plasmaglucose) £105 mg/dL, no history of DM or use of anti-diabetic medication at baseline, 79 (13%) incurred incident hyperglycemia in 1054 person-years yielding an overall rate of 7.5 cases per 100 person-years (95% CI: 6.0, 9.4), and 38 incurred incident DM in 1088 person-years, yielding an overall rate of 3.5 cases per 100 person-years (95% CI: 1.7, 3.7).
After adjustment for age and BMI, the hazard of pre-diabetes or DM among the HIV+ HAART group was 1.8 times (95% CI: 1.1, 3.0) that of the HIV- group, and the hazard of DM among the HIV+ HAART group was 3.1 times (95% CI: 1.3, 7.1) that of the HIV- group. Exposure to a HAART regimen including a PI (hazard ratio [HR] = 1.9; 95% CI: 1.1, 3.3), d4T (HR = 2.1; 95% CI: 1.1, 3.9) or efavirenz (HR = 3.9; 95% CI: 1.6, 9.5) were each significantly associated with a higher rate of incident pre-diabetes or DM compared to the HIV- group.
The study concluded that HIV+ men with HAART exposure have an increased prevalence and incidence of pre-diabetes and DM. Exposure to a HAART regimen—including PIs, d4T, or efavirenz—was associated with an apparent increased risk of hyperglycemia.
Howard and colleagues presented abstract 701, Impaired Glucose Metabolism and Antiretroviral Use Among HIV-infected Women. As with the study discussed above, many have focused on men and there is limited knowledge of the effects of HIV and its therapies on women.
They performed a 75-g oral glucose tolerance test in 125 HIV-infected and 90 at-risk HIV-uninfected women without a history of diabetes, and assessed the association of antiretroviral use and non-medication related factors with impaired glucose tolerance, diabetes mellitus, and insulin resistance (HOMA).
The median age was 45 years (range 35 to 70); 51% were black, 38% Hispanic, 10% white; 38% had a family history of diabetes mellitus and 13% reported giving birth to a baby >9 lbs; median body mass index was 28.8 kg/m2 and mean waist-to-hip ratio was 0.89; 90% had ever smoked cigarettes (median 15.0 pack-years); 68% were current smokers; 41% had a history of injection drug use with no difference by HIV status. Among HIV-infected women, 25% were HAART-naive, 23% were on HAART but protease inhibitor (PI)-naïve, and 52% were on HAART with PI. Median duration of PI use was 43 months. Median CD4 count was 481 cells/mm3.
The prevalence of diabetes (fasting glucose >=126 mg/dL or 2-hour glucose >=200 mg/dL) among all women was 6% (n = 14) and of IGT (2-hour glucose >=140 and <200) was 11% (n = 23), with no difference by HIV status, HAART, or PI use.
Mean log insulin resistance (HOMA) (_U/mL·mM) was lower among HAART-naïve HIV-infected women (0.40) compared with those on PI-HAART (0.45), non-PI HAART (0.48), or HIV-uninfected women (0.47), but this difference was not significant.
In a logistic regression model, factors independently associated with an abnormal oral glucose tolerance test (impaired glucose tolerance or diabetes mellitus) included age >=50years (ORadj 4.5, 95%CI 1.5, 13.4) and smoking (ORadj 1.7 per 10 pack-years, 95%CI 1.2, 2.4), after controlling for HIV, HAART use, PI use, race, family history of diabetes, and waist-to-hip ratio.
In a linear regression model, factors independently associated with log insulin resistance (HOMA) among HIV-infected women included body mass index (p <0.0005), Hispanic race (p = 0.047), and non-PI HAART (p = 0.04), after controlling for PI use and CD4 count.
They concluded that impaired glucose tolerance and diabetes mellitus were detected by oral glucose tolerance tests in a substantial minority of women, and were associated with traditional diabetes risk factors rather than HIV infection, PI or HAART use.
However, among HIV-infected women, non-PI HAART use was independently associated with greater insulin resistance. I think one has to be careful in interpreting this study especially given the high background of traditional risk factors and one may need a much larger sample size to reduce the impact of these confounding factors. For example, the majority of the subjects were from ethnic backgrounds that clearly have a higher rate of diabetes plus 38% had a family history of diabetes. All in all, this is a first step and further studies among women and minorities are warranted.
Nevertheless, both these studies do demonstrate that significant numbers of persons do have either diabetes or insulin resistance. There were a few studies exploring the effects of various ART. This can be quite complicated and some studies examined the effects of ART among HIV sero-negative subjects while others examined the effects among those subjects infected with HIV.
Reyataz: did not impair sugar metabolism & raise triglycerides in healthy volunteers
Investigators from Bristol-Myers-Squibb presented Abstract 702 The Effect of Atazanavir vs Lopinavir/ritonavir on Insulin-stimulated Glucose Disposal Rate in Healthy Subjects. A proposed mechanism for why protease inhibitors may be associated with the development of diabetes is via blockade of the glucose transporters that take the glucose from the bloodstream into the tissues.
Atazanavir (ATV), unlike indinavir, lopinavir, and ritonavir, appears not to block glucose transport through the glucose transporter-4 insulin-sensitive transporter in vitro. This study compared the effects of ATV and lopinavir/ritonavir (Kaletra, LPV/r) to placebo on insulin-stimulated glucose disposal rates.
This was a randomized, double-blind, cross-over study of the effect of 5 days of treatment with ATV, LPV/r, or placebo on insulin-stimulated glucose disposal in healthy HIV-negative volunteers. Each subject was studied on 2 of 3 possible treatments using the hyperinsulinemic euglycemic clamp technique (180 minutes) with >=14 days of wash-out.
Difference among groups in insulin-stimulated glucose disposal per unit of insulin and glycogen storage rate (proportion of total glucose disposal taken up by the tissue but not oxidized) was analyzed by ANOVA. They studied 30 healthy HIV seronegative adult men with median age of 35 years (range 19 to 49), mean weight of 76.4 kg (SD = 9.9), mean body mass index of 24.0 kg/m2 (SD = 2.4).
During steady-state euglycemia (60 to 180 minutes), insulin levels were raised comparably (65.4, 63.0, 63.9 mU/mL) and glucose was clamped at ~75 mg/dL under all conditions.
LPV/r decreased the mean insulin-stimulated glucose disposal per unit of insulin (M/I) by 24% compared to placebo and by 23% compared to ATV. LPV/r decreased glycogen storage rate (GSR) by 35% compared to placebo and by 38% compared to ATV.
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Treatment
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M/I
U/mL
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GSR
mg/kg*min
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Adjusted Mean ± SE
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LPV/r
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0.84
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0.37
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ATV
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0.84
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0.37
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Placebo
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0.84
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0.37
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Difference (95% CI) p-value
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LPV/r vs. ATV
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-2.26 (-3.95, -0.58) p=0.011
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-1.60 (-2.49, -0.71) p=0.001
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LPV/r vs. Placebo
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-2.33 (-4.02, -0.64) p=0.009
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-1.41 (-2.30, -0.52) p=0.003
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ATV vs. Placebo
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p=0.935
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p=0.655
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In conclusion, ATV did not reduce insulin sensitivity and had no effect on insulin-stimulated glucose disposal or GSR. In contrast LPV/r induced insulin resistance and reduced the glucose disposal per unit of insulin and glycogen storage rate. These data are consistent with in vitro studies showing that ATV does not interfere with glucose transporter-4 activity and does not induce fasting hyperinsulinemia, substantiating the findings of large clinical trials. In addition, fasting triglycerides were not affected by ATV but increased a mean of 43% on LPV/r. This is welcomed and supporting evidence that ATV is not associated with the metabolic complications as many of the other antiretroviral drugs are.
Comparative Effects of Nelfinavir & Efavirenz on Lipids & Glucose in ACTG 384 Study
The ACTG 5005s team presented partial results of a metabolic substudy of a large, randomized study (ACTG 384) which compared the nucleoside (NRTI) backbones of either AZT/3TC or d4T/ddI with EFV, NFV or combined EFV/NFV regimens. (Abstract 74: Prospective Study of Glucose and Lipid Metabolism in Antiretroviral-Naive Subjects Randomized to Receive Nelfinavir, Efavirenz, or Both Combined with Zidovudine+Lamivudine (ZDV+3TC) or Didanosine+Stavudine: A5005s, a Substudy of ACTG 384).
The primary objective of A5005s was to determine whether nelfinavir (NFV)- and efavirenz (EFV)-based therapies differ with respect to changes in fasting lipids and insulin resistance. Secondary objectives included comparisons among NRTI regimens.
Antiretroviral-naive subjects (n = 334) received NFV (99), EFV (110), or both (125) plus zidovudine (ZDV) + lamivudine (3TC) (154) or didanosine (ddI) + stavudine (d4T) (180) in a substudy of a 3x2 randomized factorial trial. Fasting samples were collected at entry, 8, 16, 32, 48, and 64 weeks. Primary analyses (Wilcoxon tests) are intent-to-treat; changes from entry are reported as median [IQR] at week 32. The EFV+NFV group was excluded from NFV vs EFV comparisons, but included in NRTI analyses.
--Lipid values (mg/dL) increased in all groups. The proportion with total-Cholesterol >200 increased from 13% to 45% at week 32 (cholesterol went up);
--those with HDL (good)-Cholesterol <40 fell from 75% to 48% (each p <0.001), so there was a negative effect on good cholesterol .
--HDL-C (positive effect on good cholesterol) increases correlated with higher HIV RNA and lower CD4 at entry (each p <0.001).
--Similar increases occurred with both NFV and EFV in total-Cholesterol (NFV 28 [9, 56], EFV 25 [9, 52], non-HDL-Cholesterol (22 [7, 52] versus 19 [0, 42]), and triglycerides (TG) (13 [-13, 56] versus 32 [-19, 76]).
--Only 6% with EFV and 5% with NFV had TG >400 at week 32.
--HDL-C increases tended to be greater with EFV (7 [2, 12]) than NFV (5 [0, 10], p = 0.11), with a more favorable change in total:HDL-C ratio with EFV (-0.4 versus 0.4, p = 0.03).
--There was some evidence of greater increases in total-Cholesterol with ddI+d4T (45 [12, 71]) versus ZDV+3TC (29 [10, 55], p = 0.07) and non-HDL-C (35 [10, 60] versus 26 [0, 52], p = 0.12). HDL-C (8 [2, 14] versus 7 [0, 12]) and TG (30 [-13, 84] versus 25 [-14, 60]) increases were similar.
--Insulin resistance (by HOMA-insulin resistance) increased over time for the whole group. From a baseline of 1.39 [0.90, 2.05], median change at week 8 was 0.20 [-0.37, 0.72] (p = 0.03); no changes were significant within any group. At week 32, the overall median increase was 0.38 [-0.22,0.97] (p = 0.002), but differences in the change in HOMA-insulin resistance between groups were minimal: NFV 0.41 [-0.37, 1.43], EFV 0.39 [-0.17, 0.82] (p = 0.9); ddI+d4T 0.32 [-0.29, 0.85], ZDV+3TC 0.40 [-0.19, 1.30] (p = 0.4).
SUMMARY
Overall, the PI NFV and the NNRTI EFV appear to have comparable effects on fasting lipids, with a better total:HDL-C ratio with EFV.
Lipids tended to be slightly more favorable with ZDV+3TC than ddI+d4T.
HDL-Cholesterol changes correlated with entry HIV disease status.
Insulin resistance worsened in the group as a whole, but did not differ between regimens.
The lack of an early increase in insulin resistance with NFV suggests that acute insulin resistance is not a PI drug class effect.
This supports earlier studies which suggested that NFV does not significantly inhibit the gluc-4 transporter system as mentioned above. Nevertheless, insulin resistance did worsen over time in a subset of subjects and further study is warranted to explore these findings.
Lipids & Sugar Metabolism Improve in NEFA Study After Switch from Protease Inhibitor to Nevirapine, Efavirenz or Abacavir Regimens
In addition, Dr. Fisac presented further data on the metabolic complications evaluated in the NEFA strudy in abstract 78, Metabolic Changes in Patients Switching from a Protease Inhibitor-Containing Regimen to Abacavir, Efavirenz,) or Nevirapine: 24-Month Results of a Randomized Study.
NEFA was an open-label randomized study comparing 3 different protease inhibitor-sparing regimens (ABC-abacavir, EFV-efavirenz, and NVP-nevirapine) in HIV+ individuals who had been previously exposed to a HAART protease inhibitor-containing regimens. A sub-study in 92 patients was conducted to evaluate the switching effect on metabolic and body composition parameters. The metabolic outcomes in 69 patients who maintained the initially allocated treatment for 24 months (ABC: n = 22; EFV: n = 21; NVP: n = 26) were presented.
Fasting serum total cholesterol, low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), triglycerides, glucose, and insulin were determined. Insulin resistance by the homeostasis model assessment and total cholesterol:HDLc ratio were also calculated.
In an overall analysis, insulin, insulin resistance, total cholesterol, LDLc, HDLc, and total cholesterol:HDLc ratio improved (baseline vs 24-month data). EFV and NVP arms showed similar metabolic benefits after 2 years of therapy.
The sample size is too small to compare individual PI-containing regimens at baseline however these results remain encouraging that metabolic complications that may be associated with certain PIs may improve after switching to a NNRTI.
Aging & HIV: diabetes found to be associated with cognitive impairment in older HIV+ individuals; perhaps, a new risk factor for older HIV+ individuals
Finally, I would like to mention a study that did not receive that much attention but one that brings up the issue on aging and how age plays into the role of HIV and its associated complications. A group of investigators from Hawaii have been following an aging population with HIV, "The Hawaii Aging with HIV Cohort". It is estimated that over 10% of newly diagnosed HIV infections occur in the population over the age of 50. Age plays a major role in the development of CHD, diabetes, hypertension and many diseases.
These investigators presented abstract 502 (Shikuma et al, Universities of Hawaii & Johns Hopkins): "Diabetes and Cognitive Functioning Among HIV Seropositive Patients. The Hawaii Aging with HIV Cohort".
The impact on aging and its association with development of dementia in HIV is unknown. The investigators took a step further and asked whether the metabolic complications associated with HIV have even more of an impact on the aging HIV-infected population.
Participants were from one of two groups (under 40 or 50+ years old) within the seropositive arm of the Hawaii Aging with HIV Cohort. Evaluations included comprehensive neuropsychological testing. Three measures of cognitive functioning were constructed from combinations of scores on neuropsychological test results standardized within our sample: an overall measure of cognitive functioning, NPZ8; a measure of memory, NPZ3-memory; and a measure of psychomotor functioning, NPZ3-psychomotor.
Trained personnel obtained medical histories including established diagnoses for diabetes (DM) using a structured interview. Data from 169 participants (73 younger and 96 older) were available for these analyses.
--Frequency of DM was 8.9% (15.6% among older and 0% among younger).
--DM was negatively associated with overall cognitive functioning (F = 19.15, p < 0.01), accounting for 11% of the variance in NPZ8 scores. DM was also negatively associated with psychomotor functioning (F = 14.16,pp < 0.01) accounting for 8% of the variance in NPZ3-psychomotor scores.
--There was no association between DM and NPZ3-memory scores.
--Controlling for age, ARV, current hypertension, current hypercholesterolemia, pack-years of smoking, ethnicity, and duration of HIV infection, did not substantially alter these results.
These data suggest that diabetes is associated with decreased overall cognitive performance and specifically psychomotor performance in patients with HIV.
Our findings are driven exclusively by diabetes in older patients and thus, if confirmed, may represent a newly identified risk factor for older seropositive patients. This risk is independent of other vascular risk factors. The underlying mechanism is not clear. While speculative, this could be associated with metabolic dysfunction and abnormalities in glucose regulation. I certainly believe further studies are needed exploring the effects of HIV and its therapies on the aging HIV-infected population as many have other traditional risk factors for metabolic and cardiac diseases and we will need to know how best to manage them.
In summary, a quote from a colleague of mine, Dr. Donald Kotler, "Insulin resistance kills. Why would anyone think having HIV would be protective?" Dr. Kotler's point is well taken. Although we do not know what the risk of progressing from insulin resistance to diabetes is among those infected with HIV, we do know insulin resistance without HIV is bad. Just as we cannot be passive and let individuals sit with high lipids and ignore markers for cardiac disease, we should be managing our HIV-infected patients with insulin resistance or diabetes as we would the general population. The question remains whether conventional therapies for diabetes will work similar in the HIV infected population and further studies are warranted exploring the pathogenesis and management of insulin resistance in this population.
Hepatitis C Increases Risk for New-onset Diabetes
Notes From Jules Levin
Researchers at the University of Washington reported at the Retrovirus Conference that HIV-infected individuals having HCV (hepatitis C virus) increased the risk for developing diabetes. They also found that African-Americans were at greater risk for developing diabetes, and that if you are older than 40 years of age the risk for developing diabetes increased. Poster 878; History of Acute Pancreatitis and Hepatitis C Virus Increase Risk of New-onset Diabetes Among HIV-Infected Patients; Crane et al). They conducted a retrospective cohort study to examine predictors of diabetes type 2 in an urban HIV clinic from 1996 to 2003.
Of 699 HIV-infected patients identified, 40 developed DM. A higher proportion of patients who developed DM had HCV infection (43% vs 23%, p <0.01), pancreatitis (13% vs 4%, p = 0.01), were African American (45% vs 17%, p <0.01), and were 40 years of age or older (55% vs 29%, p <0.01). In multivariate analysis controlling for other factors, patients with HCV infection had a 2.1-fold (95% CI:1.1 to 4.2) increase and patients with a history of pancreatitis had a 3.1-fold (95% CI: 1.1 to 9.3) increase in the odds of developing DM compared with patients without HCV or pancreatitis. African Americans had 3.0 times the odds (95%CI: 1.5 to 6.1) of DM compared with whites.
In a separate adjusted analysis each 1-year increase in age was associated with a 6% (95%CI: 1.01 to 1.1) increase in the odds of DM. CD4 cell count, HIV-1 RNA level, gender, and history of PI therapy were not significantly associated with DM. The majority of patients who developed DM had a history of acute rather than chronic pancreatitis.
HCV & Diabetes in HCV Monoinfected Individuals: HCV found to induce diabetes in mice
In the March 2004 issue of the journal Gastroenterology (volume 6, issue 3), the authors looked at mice in the laboratory who were infected by them with the hepatitis C virus to see if HCV causes insulin resistance and diabetes. They concluded that their study found that the HCV core protein induces insulin resistance in transgenic mice without gain in body weight at young age; and these results indicate a direct involvement of HCV per se in the pathogenesis of diabetes in patients with HCV infection and provide a molecular basis for insulin resistance in such a condition. Evidence has been accumulating for years that HCV can increase the risk for developing diabetes.
The study published in this month's Gastroenterology reported on research trying to elucidate the role of HCV in a possible association between diabetes and HCV infection in transgenic mice that carry the core gene of HCV. Shintani et al found that these mice developed insulin resistance. An addition of a high-calorie diet led to the development of type 2 diabetes by disrupting the balance between insulin resistance and secretion.
"The article...makes an important contribution to putting the HCV-diabetes association on a mechanistic footing, thus elevating it from a curious association to an important disease process.....The study makes a major contribution by showing that hepatic insulin resistance can be induced solely by expression of the HCV core protein, and that signaling abnormalities in the insulin receptor-IRS-1 pathway are present before the development of steatosis," write Dr. Steven A. Weinman and Dr. L. Maria Belalcazar from University of Texas Medical Branch, Galveston, in a related editorial. "In this study, the mice that developed diabetes after high-fat feeding were 4 months old and it is likely that, by that time, there was an increase in hepatic triglyceride content. Thus, it is very possible that the increased fatty deposits in the liver of the transgenic mice, together with the impairment in insulin signaling caused by the HCV core protein, led to the onset of diabetes".
Since Allison et al. (J Hepatol 1994;21:1135-1139) reported an association between HCV infection and diabetes, evidence has been accumulating connecting these 2 conditions. In such studies, HCV infection has a significantly stronger association with diabetes than hepatitis B viral infection. The variables other than HCV infection that are associated with diabetes are cirrhosis, male sex, obesity, and aging. In addition to these clinic-based, case-control studies, Mehta et al. (Ann Intern Med 2000;133:592-599) have reported the result of investigation at population level. In this cross-sectional national survey, persons 40 years or older with HCV infection were more than 3 times more likely to have type 2 diabetes than those without HCV infection. Thus, the association of HCV infection with diabetes has become closer as shown by epidemiological studies. However, there are some difficulties in establishing a definite relationship between HCV infection and diabetes on the basis of epidemiological studies; in patients, there are other numerous factors perturbing the verification of the definite relationship, such as obesity, aging, or particularly advanced liver injuries. Moreover, the biological mechanism underlying diabetes or insulin resistance in HCV infection is unknown. In vitro or cultured cell studies have a very limited utility for the study of insulin resistance or diabetes because insulin resistance is a condition that involves multiple organs, such as the skeletal muscles and liver. Thus, the use of good experimental animal model systems may be useful both in establishing a definite relationship between diabetes and HCV infection and in elucidating the role of HCV in the development of insulin resistance.
Approximately 200 million people are chronically infected with hepatitis C virus (HCV) in the world. Chronic HCV infection may lead to cirrhosis and hepatocellular carcinoma, thereby being a worldwide problem both in medical and socioeconomical aspects. In addition, chronic HCV infection is a multifaceted disease, which is associated with numerous clinical manifestations, such as essential mixed cryoglobulinemia, porphyria cutanea tarda, and membranoproliferative glomerulonephritis. Recent epidemiological studies have added another clinical condition, type 2 diabetes, to a spectrum of HCV-associated diseases. However, the establishment of a definite causative relationship between HCV infection and diabetes is hampered by the presence of other factors such as obesity, aging, or liver injury in patients with chronic HCV infection.
Type 2 diabetes is a complex, multisystem disease with a pathophysiology that includes a defect in insulin secretion, increased hepatic glucose production, and resistance to the action of insulin, all of which contribute to the development of overt hyperglycemia.8,9 Although the precise mechanisms whereby these factors interact to produce glucose intolerance and diabetes are uncertain, it has been suggested that the final common pathway responsible for the development of type 2 diabetes is the failure of the pancreatic b-cells to compensate for the insulin resistance. Hyperinsulinemia in the fasting state is observed relatively early in type 2 diabetes, but it is considered to be a secondary response that compensates for the insulin resistance. Overt diabetes occurs over time when pancreatic -cells bearing the burden of increased insulin secretion fail to compensate for the insulin resistance.
Shintani reported that in the current study, the HCV core gene transgenic mice exhibited insulin resistance as early as 1-month old, despite an apparent absence of glucose intolerance. Development of insulin resistance without any liver injury or excessive body weight gain, as shown in the current study, clearly indicates that infection of HCV per se is a cause of the development of insulin resistance. The occurrence of insulin resistance in the core gene transgenic mice as early as 1-month old also excluded the possibility that aging is a cause of insulin resistance. Nonetheless, aging could be an aggravating factor for insulin resistance. Thus, the current analysis shows a definite causal relationship between HCV infection and the development of insulin resistance.
In the glucose tolerance test, plasma glucose levels were higher at all time points including in the fasting state in the core gene transgenic mice than in control mice, although the difference was not statistically significant. In contrast, the transgenic mice exhibited a marked insulin resistance as revealed by the insulin tolerance test, as well as significantly higher basal serum insulin levels. There was a substantial increase in fasting plasma glucose levels in high-fat-diet-fed control mice compared with normal-diet-fed control mice. Feeding with a high-fat diet led to the development of overt diabetes in the transgenic mice but not in control mice. A high level of tumor necrosis factor-a, which has been also observed in human chronic hepatitis C patients, was considered to be one of the bases of insulin resistance in the transgenic mice, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1. Moreover, administration of an anti-tumor necrosis factor-a antibody restored insulin sensitivity.
Earlier studies have shown the development of hepatic steatosis in these HCV core gene transgenic mice after the age of 3 months. However, insulin resistance invariably preceded the occurrence of hepatic steatosis, indicating that insulin resistance is not a consequence of hepatic steatosis in these mice. Certainly, it is possible that insulin resistance in the core gene transgenic mice may be affected or aggravated after the occurrence of hepatic steatosis. On the other hand, insulin resistance may be one of the factors that cause hepatic steatosis, whereas the impairment of very-low-density lipoprotein (VLDL) secretion from the liver and hypo--oxidation of fatty acids are considered to be the bases of development of hepatic steatosis in the core gene transgenic mice.
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