c-peptide and HIV-Associated-Lipodystrophy-Syndrome

We examined whether plasma concentrations of nonglucose insulin secretagogues are associated with prehepatic insulin secretion rates (ISR) in nondiabetic, insulin-resistant, human immunodeficiency virus (HIV)-infected, lipodystrophic patients (LIPO). Additionally, the negative feedback of insulin on ISR was evaluated. ISR were estimated by deconvolution of plasma C-peptide concentrations during fasting (basal) and during the last 30 min of a 120-min euglycemic insulin clamp (40 mU.m(-2).min(-1)). Eighteen normoglycemic LIPO were compared with 25 normoglycemic HIV-infected patients without lipodystrophy (controls). Thirty minutes before start of the clamp, a bolus of glucose was injected intravenously to stimulate endogenous insulin secretion. Insulin sensitivity index (SiRd) was estimated from glucose tracer analysis. LIPO displayed increased basal ISR (69%), clamp ISR (114%), basal insulin (130%), and clamp insulin (32%), all P < or = 0.001, whereas SiRd was decreased (57%, P < 0.001). In LIPO, ISRbasal correlated significantly with basal insulin, alanine, and glucagon (all r > 0.65, P < 0.01), but not with glucose. In control subjects, ISR(basal) correlated significantly with insulin, glucagon, and glucose (all r > 0.41, P < 0.05), but not with alanine. In LIPO, ISRclamp correlated significantly with clamp free fatty acids (FFA), alanine, triglyceride, and glucagon (all r > 0.51, P < 0.05). In control subjects, ISRclamp correlated with clamp triglyceride (r = 0.45, P < 0.05). Paradoxically, in LIPO, ISRclamp correlated positively with clamp insulin (r = 0.68, P < 0.01), which suggests an absent negative feedback of insulin on ISR. Our data support evidence that lipodystrophic, nondiabetic, HIV-infected patients exhibit increased ISR, which can be partially explained by an impaired negative feedback of insulin on beta-cells and an increased stimulation of ISR by FFA, alanine, triglyceride, and glucagon.

Topics: Adipose Tissue; Adult; Alanine; Anthropometry; Blood Glucose; Body Composition; Body Mass Index; C-Peptide; Feedback; Glucagon; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Triglycerides

Low-dose growth hormone (GH) administration has been suggested as a treatment for HIV-lipodystrophy.. Postglucose GH-secretion, kinetics of insulin-like growth factors (IGFs), insulin, and glucose metabolism were examined in six male HIV-infected lipodystrophic patients (two normal-weight patients with normal glucose-tolerance (NGT), two normal-weight with impaired glucose-tolerance (IGT), and two obese patients with diabetes (DM)) during a 16 weeks open-labelled pilot-study of low-dose GH, 0.7 mg/day.. DM, compared to NGT and IGT, displayed an impaired rebound of GH during a 5h oral glucose-tolerance test. Near lower normal limits in all patients before GH-therapy, total and free IGF-I increased between 87 and 152% during the GH-therapy (P<0.001), approaching upper normal limits in all patients with the highest incremental percentages shown in DM. A slight and temporary reduction in insulin sensitivity was caused by a reduction in non-oxidative glucose metabolism (n=5). GH-administration reduced hepatic extraction of insulin alleviating the demand for insulin secretion (n=5). No adverse effects of GH were detected.. As judged from effects on circulating IGF-I, glucose metabolism, and insulin kinetics, 0.7 mg/day of GH may be expedient for treatment of HIV-infected males with lipodystrophy. Whether the patients' glucose metabolic status matters for the IGF-response to low-dose GH-therapy awaits further investigation.

Topics: Antiretroviral Therapy, Highly Active; C-Peptide; Fatty Acids, Nonesterified; Glucose; Glucose Tolerance Test; Growth Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Secretion; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Middle Aged; Oxidation-Reduction; Time Factors

We examined whether insulin-resistant lipodystrophic HIV-infected patients with known high fasting prehepatic insulin secretion rates (FISRs) displayed alterations in first-phase prehepatic insulin response to intravenous glucose (ISREG0-10 min).. Eighteen normoglycaemic lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp technique. The disposition index (Di=ISREG0-10 min x SIRd) was calculated to estimate the beta-cell response relative to insulin sensitivity.. FISR was increased by 69% (P<0.001), whereas median Di was decreased by 75% (P<0.01), primarily as a result of a reduction of SI(Rd) by 60% (P<0.001) in LIPO patients compared with controls. Three LIPO groups were identified arbitrarily according to their FISR and ISREG0-10 min values relative to those of controls. Four LIPO patients displayed high FISR [+3 standard deviations (SD), P<0.001], high ISREG0-10 min (+3 SD, P<0.001) and low SIRd (P<0.01), suggesting an intact B-cell capacity to compensate insulin resistance; six LIPO patients exhibited high FISR (+3SD, P<0.001), low ISREG0-10min (-1 SD, P=0.01), and low SIRd (P<0.01), suggesting depletion of readily releasable insulin stores; the remaining eight LIPO patients and controls displayed identical FISR and ISREG0-10 min. Increased concentrations of the nonglucose insulin secretagogues triglyceride (+124%), alanine (+35%) and glucagon (+88%), and also lactate (+96%) and tumour necrosis factor (TNF)-alpha (+62%) were observed in the 10 LIPO patients with aberrations in FISR and ISREG0-10 min compared with the remaining HIV-infected patients (all P<0.05).. Plasma triglyceride, alanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients.

Topics: Adult; Alanine; C-Peptide; Case-Control Studies; Glucagon; Glucose; Glucose Clamp Technique; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Infusions, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Lactates; Male; Middle Aged; Stimulation, Chemical; Triglycerides; Tumor Necrosis Factor-alpha

Highly active antiretroviral therapy has been associated with lipodystrophy in adults. Much is unknown about its characteristics, especially in children.. To obtain an objective case definition of the lipodystrophy syndrome.. This was a cross-sectional study. One investigator rated clinical lipodystrophy. Body composition was measured using body mass index, skin fold thickness and circumference of arm, leg, waist and hip. Samples for human immunodeficiency virus (HIV)-1 RNA, CD4 cell count, fasting lipids and glucose variables were drawn. HIV-infected children with lipodystrophy were compared with HIV-infected children without lipodystrophy (controls).. Thirty-four children were included: 28 controls, 2 nonassigned, and 4 with the lipoatrophic phenotype. Lipohypertrophy or mixed syndrome were not observed. All children with lipoatrophy were pubertal; they had used stavudine and didanosine longer. Children with lipoatrophy had significantly smaller arm and leg circumference, and their skin folds were thinner. The torso-to-arm ratio was 3 times higher in lipoatrophic children, but the difference did not reach significance. The waist-to-hip ratio was higher (P = 0.005). None of the laboratory values differed significantly between the two groups, but all children with lipoatrophy had an increased C-peptide level above the upper limit of normal. All children with lipoatrophy could be distinguised from controls by an increased C-peptide level, a waist-to-hip ratio z score of 1 standard deviation or higher and a sum of skin folds z score below -1 standard deviation.. All children with lipoatrophy can be distinguished by using anthropometric measurements and C-peptide measurement in serum. This method is simple, readily available and inexpensive.

Topics: Adolescent; Anthropometry; Antiretroviral Therapy, Highly Active; Body Composition; C-Peptide; Child; Child, Preschool; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Infant; Male

We aimed to investigate whether the insulin precursors, intact (IP) and 32-33 split proinsulin (SP), which are elevated in states of insulin resistance and predict type 2 diabetes, would be elevated in human immunodeficiency virus (HIV)-infected patients with lipodystrophy (LIPO).. Forty-three normoglycaemic HIV-infected patients [18 LIPO and 18 without lipodystrophy (NONLIPO) receiving antiretroviral drugs, and seven patients naïve to antiretroviral drugs (NAIVE)] were examined. Insulin precursors were measured during fasting, during an intravenous glucose tolerance test and during a hyperinsulinaemic-euglycaemic clamp, respectively. Insulin secretion rates (ISR) were determined by deconvolution of C-peptide concentrations. Disposition index (DI) was calculated as insulin sensitivity (Si(RD)) multiplied by the first-phase insulin response to intravenous glucose.. LIPO exhibited increased fasting IP and SP (P < 0.05), a higher proportion of elevated fasting IP (3.1 pmol L(-1), 66% vs. 33% and 28%, P < 0.05) and SP (7.2 pmol L(-1), 50%, 11% and 0%, P < 0.01), reduced Si(RD) (> 50%, P < 0.001) and increased ISR (P < 0.001) compared with NONLIPO and NAIVE. Fasting SP and IP correlated positively with ISR (P < 0.001) and inversely and hyperbolically with Si(RD) (P < 0.001). Fasting SP/insulin ratio correlated inversely with Si(RD) (P < 0.05). Incremental IP + SP/insulin ratio after an intravenous glucose bolus correlated inversely with DI (P < 0.01), but did not differ between study groups.. Proinsulin appeared to be increased in HIV-lipodystrophy, but no more than caused by the increased ISR. Nevertheless, the inverse correlations between SP/insulin ratio versus Si(RD) and incremental total proinsulin/insulin ratio versus DI may argue for a subtle beta-cell dysfunction in those patients with insulin resistance and low DI.

Topics: Adult; Antiretroviral Therapy, Highly Active; Blood Glucose; Body Composition; C-Peptide; Fasting; Glucose Tolerance Test; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperlipidemias; Insulin; Insulin Resistance; Male; Middle Aged; Proinsulin

We investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV-infected patients on highly active antiretroviral therapy (HAART).. Eighteen HIV-infected male patients (six lipodystrophic and 12 nonlipodystrophic) with normal glucose tolerance (NGT) were compared with 10 HIV-infected male patients (eight lipodystrophic and two nonlipodystrophic) with IGT. Plasma concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations.. The incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared with NGT patients (1455+/-422 vs. 409+/-254 pmol/L/180 min, respectively; P<0.05), whereas the incrAUC for GIP did not differ between the study groups (7689+/-1097 vs. 8041+/-998 pmol/L/180 min, respectively; not significant). In pooled study groups, the GIP incrAUC correlated positively with the ISR incrAUC without adjustment (r=0.38, P<0.05) and following adjustment for glucose incrAUC (r=0.49, P<0.01).. Our data suggest: (1) that glucose-intolerant, HIV-infected male patients may display enhanced GLP-1 responses to oral glucose compared with normal glucose-tolerant HIV-infected male patients, which may represent a compensatory mechanism rather than explain the IGT; (2) that the GIP response may be associated with ISR independently of plasma glucose in nondiabetic HIV-infected males on HAART.

Topics: Adult; Analysis of Variance; Antiretroviral Therapy, Highly Active; Antiviral Agents; Area Under Curve; Blood Glucose; Body Composition; C-Peptide; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Peptide Fragments; Protein Precursors

Highly active antiretroviral therapy (HAART) has dramatically reduced HIV-related mortality, but is associated with severe metabolic adverse events, such as lipodystrophy and insulin resistance, the mechanisms of which are unknown. Adiponectin is a adipocytokine that is decreased in insulin resistant conditions. In mice, adiponectin decreases liver and muscle fat content and enhances insulin sensitivity. We determined serum adiponenctin and adiponectin mRNA concentrations in subcutaneous adipose tissue in HIV-positive HAART-treated patients with (HAART+LD+, n = 30) and without lipodystrophy (HAART+LD-, n = 13). The HAART+ LD+ group had significantly less subcutaneous and more intra-abdominal fat than the HAART+LD- group. Liver fat content (spectroscopy), serum insulin, C-peptide and triglyceride concentrations were significantly higher, and HDL cholesterol concentration lower in the HAART+LD+ than the HAART+LD- group. Serum adiponectin (3.4 +/- 0.4 vs 8.5 +/- 1.0 micro g/mL, p < 0.001) and adiponectin mRNA concentration in subcutaneous adipose tissue (7 +/- 1 x 10(-4) vs 24 +/- 6 x 10(-4), p < 0.001) were significantly lower in the HAART+LD+ than the HAART+LD- group. Both serum adiponectin and mRNA concentrations correlated closely with features of insulin resistance, including liver fat content. These data suggest that the decreased production of adiponectin in lipoatrophic adipose tissue may contribute to hepatic insulin resistance in these patients.

Topics: Abdomen; Actins; Adiponectin; Adipose Tissue; Adult; Antiretroviral Therapy, Highly Active; Body Composition; C-Peptide; Cholesterol, HDL; Female; Gene Expression; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Proteins; RNA, Messenger; Triglycerides