Fariba Shojaee-Moradie

A comparison of the effects of IGF-I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers

Abstract. The metabolic and cardiovascular effects of recombinant human IGF‐I were compared to insulin in six normal subjects. Subjects were studied twice and intravenously received an infusion of [6,6‐2H2]glucose (0–480 min) and in random order either IGF‐I 20μg kg‐1 h‐1 (43.7 pmol kg‐1 min‐1) or insulin 0.5 mU kg‐1 min‐1 (3.4 pmol kg‐1 min‐1) with an euglycaemic clamp. One subject was withdrawn following a serious adverse event. During the IGF‐I infusion glucose appearance rate (Ra) decreased from 1.79 ± 0.13 at baseline (150–180 min) to 0.35 ± 0.26 mg kg‐1 min‐1 (P < 0.01) at 360min, and glucose utilization rate (Rd) increased from 1.79 ± 0.28 to 4.17 ± 0.84 mg kg‐1 min‐1 (P < 0.01). There was no change in free fatty acids (FFA) and an increase (percentage change from pre‐infusion mean) in cardiac output + 37.3%± 9% (P < 0.01), heart rate + 13%± 2% (P < 0.01) and stroke volume + 21%± 7% (P < 0.05). During the insulin infusion glucose Ra decreased from 1.89 ± 0.13 to 0.34 ± 0.33 mg kg‐1 min‐1 (P < 0.01) and FFA from 0.546 mmoll‐1 to 0.198 mmoll‐1 (P < 0.01), glucose Rd increased from l.89 ± 0.18 to 5.41 ± l.47mg kg‐1 min‐1 (P < 0.01) and there were no significant changes in the cardiovascular variables.

The Effects of Growth Hormone and/or Testosterone on Whole Body Protein Kinetics and Skeletal Muscle Gene Expression in Healthy Elderly Men: A Randomized Controlled Trial

CONTEXT Alterations of protein turnover may contribute to the progressive decline of muscle mass with aging. OBJECTIVE Our objective was to examine the effects of near-physiological recombinant human GH and/or testosterone (T) administration to older men on whole body protein kinetics and muscle gene expression. DESIGN, SETTINGS, AND PARTICIPANTS A 6-month randomized, double-blind, placebo-controlled trial in 21 healthy elderly men aged 65-75 yr, was performed. Participants were randomized to receive placebo GH and placebo T, rhGH and placebo T (GH), T and placebo GH (T), or rhGH and T (GHT). INTERVENTIONS The leucine rate of appearance (index of proteolysis), nonoxidative leucine disposal rate (an index of protein synthesis), and leucine oxidation rate were measured with an infusion of l-[1-(13)C] leucine. Muscle biopsies for the measurement of gene expression were performed. Body composition and aerobic capacity (maximal oxygen capacity) were measured. RESULTS Serum IGF-I levels increased significantly with GH and GHT (P < 0.001) compared with placebo. T increased significantly only in the T group (P = 0.028). Leucine rate of appearance and nonoxidative leucine disposal rate increased with GH (P = 0.015, P = 0.019) and GHT (P = 0.017, P = 0.02), but leucine oxidation did not change significantly in any treatment group. Midthigh muscle mass and maximal oxygen capacity increased (P < 0.04) with GHT only. Expression of muscle function genes did not change significantly, but the within-group comparisons revealed a significant increase of androgen receptor expression in the GHT group (P = 0.001). CONCLUSION This study showed that 6-month treatment with low-dose GH alone or with T in healthy elderly men produces comparable increments in whole body protein turnover and protein synthesis.

Quantitative measurement of 3-O-methyl-D-glucose by gas chromatography-mass spectrometry as a measure of glucose transport in vivo.

Existing methods of measuring glucose kinetics are subject to errors. There is considerable interest in improved methods of measuring glucose kinetics to allow the development of new regimes for the treatment of diabetes mellitus. 3-O-Methyl-D-glucose is transported but not metabolized and therefore allows independent estimation of transport parameters. We describe a method by which 3-O-methyl-D-glucose in plasma samples can be measured in protocols during which glucose flux is assessed with simultaneous use of two isotopically labeled glucoses to quantitate and validate measurements of the rate of glucose appearance and disappearance. Quantitative gas chromatographic/mass spectrometric (GC/MS) analysis of 3-O-methyl-D-glucose, D-glucose, D-[U-13C] glucose and D-[6,6-2H2] glucose in human plasma using methoxime-trimethylsilyl ether derivatives is described. Measurements of all four derivatives were performed together in a small sample volume (50 microliters) with high precision. The intra-assay (inter-assay) coefficients of variation at an isotope content of 0.25 atom% excess for D-[6,6-2H2] glucose, D-[U-13C] glucose and 3-O-methyl-D-glucose were 0.8% (1.0%), 0.5% (4.0%) and 0.1% (3.7%), respectively. This method provides the basis for quantitative estimation of parameters of glucose kinetics in man and the rates of glucose flux across the cell membrane.

Incomplete suppression of hepatic glucose production in non-insulin dependent diabetes mellitus measured with [6,6-2H2]glucose enriched glucose infusion during hyperinsulinaemic euglycaemic clamps

Abstract.

Effects of chloroquine on the dyslipidemia of non-insulin-dependent diabetes mellitus

The effects of 3-day oral chloroquine phosphate treatment administered at a dosage of 250 mg four times daily on fasting serum levels of lipids, lipoproteins, and apolipoproteins were studied in 20 patients with non-insulin-dependent diabetes mellitus (NIDDM). Chloroquine reduced the fasting serum concentrations of total cholesterol (6.16 +/- 0.31 to 5.67 +/- 0.31 mmol/L, P < .05), low-density lipoprotein (LDL) cholesterol (4.38 +/- 0.35 to 3.93 +/- 0.32 mmol/L, P < .05), and apolipoprotein (apo) B (1.46 +/- 0.08 to 1.24 +/- 0.06 g/L, P < .01), and the ratio of apo B to apo A-I (0.81 +/- 0.05 to 0.71 +/- 0.03, P < .05). Chloroquine also caused a decrease in fasting plasma glucose levels (11.1 +/- 0.5 to 9.2 +/- 0.4 mmol/L, P < .01) and an increase in fasting plasma insulin levels (0.12 +/- 0.01 to 0.14 +/- 0.01 nmol/L, P < .01). The decrease in total cholesterol and apo B levels correlated with the increase in fasting plasma insulin levels (r = .35, P = .04 and r = .33, P = .03, respectively), but not with changes in plasma levels of glucose or nonesterified fatty acids (NEFA). This study demonstrates that 3 days of oral chloroquine treatment improves abnormalities of lipoprotein metabolism in patients with NIDDM. This may be due to an increase in insulin levels, but there also appears to be a more direct effect of the drug on apo B metabolism.

Effects of insulin-like growth factor-I (IGF-I), insulin and combined IGF-I-insulin infusions on protein metabolism in dogs.

Abstract The effect of infusions of recombinant insulin‐like growth factor‐I (IGF‐I) (34, 103 or 688 pmol min‐1 kg‐1), insulin (3·4, 10·3 or 68·8 pmol min‐1 kg‐1) or combined infusions (34 pmol IGF‐I+ 3·4 pmol min‐1 kg‐1 insulin or 103 pmol IGF‐I+ 3·4 pmol min‐1 kg‐1 insulin) on protein metabolism, using an infusion of [1‐14C] leucine was investigated in anaesthetized fasted dogs. Leucine concentration, production rate (measure of protein degradation), oxidation rate and non‐oxidative disappearance rate (measure of protein synthesis) were decreased in a similar dose dependent manner by the IGF‐I and insulin infusions (P <0·01). The decrease in these measurements of leucine metabolism were greater following 34 pmol IGF‐I + 3·4 pmol insulin than with either component infused alone (P <0·05). Free fatty acid concentrations were decreased by all insulin doses (P < 0·01) but only by 103 and 688 pmol min‐1 kg‐1 insulin‐like growth factor (P < 0·05, P < 0·01). These data demonstrate that IGF‐I, like insulin, has a dose dependent effect on protein metabolism and that combined insulin and IGF‐I infusions have additive effects on protein metabolism.

Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs.

SummaryInsulin analogues with relatively greater effect on hepatic glucose production than peripheral glucose disposal could offer a more physiological approach to the treatment of diabetes mellitus. The fact that proinsulin exhibits this property to a minor degree may suggest that analogues with increased molecular size may be less able than insulin to obtain access to peripheral receptor sites. Covalent insulin dimers have previously been shown to possess lower hypoglycaemic potencies than predicted by their in vivo receptor binding affinities. Reduced rates of diffusion to peripheral target tissues-might be an explanation for the lower in vivo potency compared to insulin. To test the relative hepatic and peripheral effects of covalent insulin dimers, glucose clamp procedures with D-[3-3H] glucose tracer infusions were used in anaesthetised greyhounds to establish dose-response curves for rates of hepatic glucose production and glucose disposal with insulin, NαB1, NαB′ 1,-suberoyl-insulin dimer, and NεB29, NεB′ 29,-suberoyl-insulin dimer. With NαB1, NαB′ 1,-suberoyl-insulin dimer molar potencies relative to insulin were 68%, (34–133) (mean and 95% fiducial limits), for inhibition of hepatic glucose production and 14.7%, (10.3–20.9) for glucose disposal. With NεB29,NεB′ 29,-suberoyl-insulin dimer potencies were 75%, (31–184) and 2.5%, (1.5–4.3), for inhibition of hepatic glucose production and for glucose disposal, respectively. The demonstration that both dimers exhibit a significantly greater effect on glucose production than on glucose disposal supports the suggestion that analogues with increased molecular size may exhibit reduced ability to gain access to peripheral target cells.

A comparison of the effects of insulin-like growth factor-I, insulin and combined infusions of insulin and insulin-like growth factor-I on glucose metabolism in dogs

Abstract. The effect of infusions of recombinant insulin‐like growth factor‐I (IGF‐I) (34, 103 or 688pmol kg‐1min‐1), insulin (3.4, 10.3 or 68.8pmol kg‐1min‐1) or combined infusions (34pmol IGF‐I+ 3–4pmol kg‐1 min‐1 insulin or 103pmol IGF‐I + 3–4pmolkg‐1 min‐1 insulin) on glucose metabolism was investigated in dogs using a [3‐3H]‐glucose infusion and euglycaemic clamp. All insulin doses decreased glucose production rate (Ra) in a dose‐dependent manner (P<0.05). All IGF‐I doses decreased glucose Ra (P < 0.05) but this decrease was not dose dependent. The decrease in glucose Ra with the combined infusion of 34pmolkg‐1min‐1 IGF‐I + 3–4pmolkg‐1min‐1 insulin was greater than 34 pmol kg‐1 min‐1 IGF‐I (P < 0.05) but not different from 3.4 pmol kg‐1 min‐1 insulin. All insulin and IGF‐I doses increased glucose utilization rate (Rd) in a dose‐dependent manner (P < 0.01). The increase in glucose utilization was greater following both combined infusions than with either component infused alone (P < 0.05). Although at the doses selected, insulin and IGF‐I had similar effects on glucose utilization with additive effects when the two peptides were combined, IGF‐I was less effective than insulin in suppressing glucose production.

Acute regulation of plasma leptin by isoprenaline in lean and obese fasted subjects

Aim:  In human obesity, there is some evidence for impaired adrenergic sensitivity with respect to catecholamine‐induced lipolysis. The β‐adrenoceptor agonist isoprenaline has been shown to suppress plasma leptin levels in lean humans in vivo. We hypothesized that a reduced adrenergic sensitivity in obese humans would result in impaired suppression of leptin secretion.

Relationships between the Structure of Insulin and its Physiological Effects

Elucidation of the structure of insulin has provided opportunities to explain its physiological properties. Following secretion directly into the hepatic portal vein, which flows directly to the liver, it acts initially to modulate hepatic glucose output, an effect primarily responsible for glucose homeostasis. Only 50% of secreted insulin passes from the liver to the other tissues where it has a role in controlling lipolysis and glucose uptake particularly after meals. In evolutionary terms selection pressure may have acted to optimize the affinity of the insulin to insulin receptor interaction in order to define the most appropriate relative hepatic to peripheral ratio of insulin action. Therapeutically insulin is given subcutaneously. This unphysiological route results in relative under-exposure of the liver to insulin with peripheral hyperinsulinaemia. By exploiting the peripheral capillary endothelium as a molecular sieve it is proving possible to design insulin analogues which compensate for this imbalance.