[Show abstract][Hide abstract] ABSTRACT: Mice heterozygous for a signalling-deficient leptin receptor (Leprdb/+(db/+)) are widely used as a model of gestational diabetes that results in poor fetal outcomes. This study investigated the importance of fetal genotype (db/+) relative to abnormal maternal metabolism for placental function and therefore fetal growth and offspring health. Wild type (wt) and db/+ females were mated to db/+ and wt males respectively generating litters of mixed genotype. Placentas and fetuses were weighed at E18.5; offspring weight, hormone levels, glucose tolerance and blood pressure were assessed at 3 and 6 months. Pregnant db/+, but not wt, dams had impaired glucose tolerance. db/+ placentas and fetuses were heavier than wt but the maternal environment had no effect; wt placentas/fetuses from db/+ mothers were no bigger than wt placentas/fetuses carried by wt mothers. Postnatal weight gain, glucose metabolism and leptin levels were all influenced by offspring genotype. However maternal environment affected aspects of offspring health as wt male offspring born to db/+ dams were heavier and had worse glucose tolerance than the sex-matched wt offspring of wt mothers. Blood pressure was not affected by maternal or offspring genotype. These data reveal that studies using the db/+ mouse to model outcomes of pregnancy complicated by gestational diabetes should be mindful of the genetically predisposed fetal/post-natal overgrowth. Although inappropriate for dissecting the effect of maternal hyperglycemia on the contribution of placental function to macrosomia, the db/+ mouse may prove useful for investigating mechanisms underlying programming of suboptimal postnatal weight gain and glucose metabolism by an adverse maternal metabolic environment.
[Show abstract][Hide abstract] ABSTRACT: The rapid rise in obesity, metabolic syndrome and type 2 diabetes is one of the major healthcare problems of the Western world. Affected individuals are often treated with statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG CoA] reductase inhibitors) to reduce circulating cholesterol levels and the risk of developing cardiovascular disease; given the evolving demographic profile of these conditions, such drugs are increasingly prescribed to women of reproductive age. We have previously shown that exposure of placental tissue to statins inhibits the action of insulin-like growth factors (IGF)-I and ÐII which are key regulators of trophoblast proliferation and placental development. N-linked glycans in the IGF receptor, IGF1R, influence its presentation at the cell surface. This study aimed to determine whether statins, which are known to affect N-glycosylation, modulate IGF1R function in placenta. Treatment of first trimester villous tissue explants with statins (pravastatin or cerivastatin) or inhibitors of N-glycosylation (tunicamycin, deoxymannojirimycin or castanospermine) altered receptor distribution in trophoblast and attenuated proliferation induced by IGF-I or IGF-II (Ki67; p<0.05, n=5). Decreased binding of Phaseolus vulgaris lectin and phytohaemagglutinin to IGF1R immunoprecipitated from treated explants demonstrated reduced levels of complex N-linked glycans. Co-incubation of tissue explants with statins and farnesyl pyrophosphate (which increases the supply of dolichol intermediates), prevented statin-mediated disruption of IGF1R localisation and reversed the negative effect on IGF-mediated trophoblast proliferation. These data suggest that statins attenuate IGF actions in the placenta by inhibiting N-linked glycosylation and subsequent expression of mature IGF1R at the placental cell surface.
Molecular Human Reproduction 10/2014; · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To design, deliver and evaluate IGT Care Call, a telephone service providing a 6 month lifestyle education programme for people with impaired glucose tolerance (IGT).
Primary Care Diabetes 08/2014; · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin-like growth factors (IGF) regulate fetal growth through their effects on placenta. Their actions are influenced by IGF binding protein-1. Phosphorylated IGFBP-1 (pIGFBP-1) has high affinity for IGF-I and usually inhibits IGF-I activity but during pregnancy, it is de-phosphorylated to generate lower affinity isoforms and consequently, increased IGF bioavailability. Here we investigate the role of placenta in this process.
Our data show that term human placental explants, but not their conditioned medium, can de-phosphorylate IGFBP-1 through the action of placental alkaline phosphatase (PLAP), suggesting a mechanism for the control of IGF-I bioavailability and action at the maternal/fetal interface.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Insulin-like growth factor (IGF) levels, their binding proteins (IGFBPs), and high-dose statin therapy, have all been linked to the development of diabetes. We aimed to identify whether atorvastatin caused dose-related changes in IGF proteins. DESIGN AND METHODS: We measured IGF1, IGF2, IGFBP1 and IGFBP3 concentrations at baseline, 6 months and 12 months in PANDA trial participants with type 2 diabetes randomised to 10mg (n=59) vs 80mg (n=60) of atorvastatin (N=119; mean (SD): age 64(10) years; 83% male; HbA1c 61(10) mmol/mol; blood pressure 131/73 mmHg. RESULTS: Atorvastatin was associated with overall reductions in circulating IGF1, IGF2 and IGFBP3 concentrations. The adjusted mean (95% CI) between-group differences that indicate dose-related changes in IGF proteins were not significant for: IGF1: -3 (-21 to 14) ng/ml; IGF2: -23 (-65 to 18) ng/ml; and IGFBP3: -0.34 (-0.71 to 0.03) µg/ml; negative values indicating numerically greater lowering with high-dose). The IGFBP1 concentration did not change overall with atorvastatin therapy overall but the adjusted mean (95% CI) between-group difference indicating a dose-related change in log IGFBP1 was highly significant -0.41 (-0.69 to 0-0.13, p=0.004). CONCLUSION: IGF1, IGF2 and IGFBP3 concentrations all decreased following atorvastatin therapy. A differential effect of low vs high dose atorvastatin on IGFBP1 concentrations was observed with likely implications for IGF bioavailability. The dose-related differential impact of atorvastatin treatment on concentration of IGF proteins merits investigation as a mechanism to explain the worsening of glucose tolerance with statin therapy.
European Journal of Endocrinology 01/2013; · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin-like growth factors are implicated in the development of diabetic nephropathy. IGF-binding protein 2 (IGFBP2) and IGF2 are expressed in the kidney, but their associations with diabetic nephropathy are unclear. We therefore tested the hypothesis that circulating levels of IGF2 and IGFBP2 predict longitudinal renal function in individuals with type 2 diabetes.
IGFBP2 and IGF2 measurements were performed in 436 individuals (263 males) with type 2 diabetes. Linear mixed-effect regression analysis was used to model the relationship between plasma IGFBP2 concentration and longitudinal changes in estimated glomerular filtration rate (eGFR) over an 8-year period. Analyses were also performed for IGF1, IGF2, IGFBP1 and IGFBP3 concentrations as predictors of longitudinal renal outcomes.
High IGFBP2 concentration at baseline was associated with a decreased eGFR over an 8-year period (β=-0.02, (95% confidence interval -0.03 to -0.01), P<0.001). High IGFBP1, IGFBP2 and IGFBP3 were also associated with low baseline eGFR concentration.
This study demonstrates that IGFBP2 is a predictor of longitudinal deterioration of renal function in type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Vascular calcification is strongly linked with increased morbidity and mortality from cardiovascular disease. Vascular calcification is an active cell-mediated process that involves the differentiation of vascular smooth muscle cells (VSMCs) to an osteoblast-like phenotype. Several inhibitors of this process have been identified, including insulin-like growth factor-I (IGF-I). In this study, we examined the role of the IGF receptor (IGFR) and the importance of IGFR glycosylation in the maintenance of the VSMC phenotype in the face of factors known to promote osteogenic conversion. IGF-I (25 ng/ml) significantly protected VSMCs from β-glycerophosphate-induced osteogenic differentiation (p < 0.005) and mineral deposition (p < 0.01). Mevalonic acid depletion (induced by 100 nm cerivastatin) significantly inhibited these IGF protective effects (p < 0.01). Mevalonic acid depletion impaired IGFR processing, decreased the expression of mature IGFRs at the cell surface, and inhibited the downstream activation of Akt and MAPK. Inhibitors of N-linked glycosylation (tunicamycin, deoxymannojirimycin, and deoxynojirimycin) also markedly attenuated the inhibitory effect of IGF-I on β-glycerophosphate-induced mineralization (p < 0.05) and activation of Akt and MAPK. These results demonstrate that alterations in the glycosylation of the IGFR disrupt the ability of IGF-I to protect against the osteogenic differentiation and mineralization of VSMCs by several interrelated mechanisms: decreased IGFR processing, reduced IGFR cell-surface expression, and reduced downstream signaling via the Akt and MAPK pathways. IGF-I thus occupies a critical position in the maintenance of normal VSMC phenotype and protection from factors known to stimulate vascular calcification.
Journal of Biological Chemistry 03/2011; 286(19):16623-30. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Illness and treatment perceptions are vital for people self-managing co-morbid conditions with associated cardiovascular disease, such as type 2 diabetes (T2D). However, perceptions of a co-morbid condition and the use of multiple medicines have yet to be researched. This study investigated the illness and treatment perceptions of people with co-morbid T2D. The Brief Illness Perception Questionnaire (repeated for T2D, hypertension, and hyperlipidemia) and the Beliefs about Medicines Questionnaire Specific Concerns Scales (repeated for Oral hypoglycemic agents, anti-hypertensive medicines, and statins) were sent to 480 people managing co-morbid T2D. Data on the number of medicines prescribed were collected from medical records. Significantly different perceptions were found across the illnesses. The strongest effect was for personal control; the greatest control reported for T2D. Illness perceptions of T2D differed significantly from perceptions about hyperlipidemia. Furthermore, illness perceptions of T2D also differed from perceptions of hypertension with the exception of perceptions of illness severity. Hypertension and hyperlipidemia shared similar perceptions about comprehensibility, concerns, personal control, and timeline. Significant differences were found for beliefs about treatment necessity, but no difference was found for treatment concerns. When the number of medicines was taken as a between-subjects factor, only intentional non-adherence, treatment necessity beliefs, and perceptions of illness timeline were accounted for. Co-morbid illness and treatment perceptions are complex, often vary between illnesses, and can be influenced by the number of medicines prescribed. Further research should investigate relationships between co-morbid illness and treatment perception structures and self-management practices.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 01/2011; 4:127-35.
[Show abstract][Hide abstract] ABSTRACT: A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear.
The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR.
We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients.
Journal of cardiac failure 09/2010; 16(9):761-8. · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Type 2 diabetes (T2D) is a common, polygenic chronic disease with high heritability. The purpose of this whole-genome association study was to discover novel T2D-associated genes. We genotyped 500 familial cases and 497 controls with >300,000 HapMap-derived tagging single-nucleotide-polymorphism (SNP) markers. When a stringent statistical correction for multiple testing was used, the only significant SNP was at TCF7L2, which has already been discovered and confirmed as a T2D-susceptibility gene. For a replication study, we selected 10 SNPs in six chromosomal regions with the strongest association (singly or as part of a haplotype) for retesting in an independent case-control set including 2,573 T2D cases and 2,776 controls. The most significant replicated result was found at the AHI1-LOC441171 gene region.
The American Journal of Human Genetics 08/2007; 81(2):338-45. · 10.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin-like growth factor (IGF)-I and IGF-II are important in the regulation of metabolism and growth. We previously reported in normoglycemic individuals of normal weight that low circulating IGF-II predicts future weight gain. We subsequently investigated whether such relationships persisted in circumstances of type 2 diabetes.
In 224 subjects with type 2 diabetes we assessed the association between baseline IGF-II levels and risk of weight gain (>2.0 kg) at the 5-year follow-up.
At follow-up, 90 participants (40.2%) gained more than 2.0 kg in body weight. For subjects (body mass index <26) at baseline, mean IGF-II levels were significantly lower in those who gained more than 2 kg in weight than in subjects of stable weight, 454 ng/mL (95% confidence interval 349-559) versus 620 ng/mL (534-705) (F=7.4, P=.01). For this subgroup low circulating IGF-II at baseline strongly correlated with weight gain (Spearman rho=-0.52, P <.001). With increasing weight, the relationship no longer prevailed. Logistic regression showed that for body mass index less than 26, individuals at baseline for each 100 ng/mL increase in baseline IGF-II there was a 47% decreased risk of gaining 2.0 kg or more in weight. Adjustment for treatment group did not materially alter this relationship. There was no difference in baseline IGF-II by treatment group. There was no difference between the group with weight gain and the group with stable weight in those who additionally received insulin or sulfonylurea treatment in the 5 years between the baseline visit and the follow-up.
In subjects of normal weight with type 2 diabetes, baseline IGF-II concentration is inversely related to future weight gain, independent of treatment effect, strengthening the putative role for IGF-II in regulating fat mass. We propose that IGF-II measurement has potential utility in this group for targeting such individuals for early intervention.
The American journal of medicine 03/2006; 119(2):167.e9-15. · 5.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diabetes mellitus and chronic kidney disease (CKD) are common and exhibit synergistic associations with premature mortality. Current diabetes guidelines in the UK recommend annual urinary albumin and serum creatinine determinations to screen for diabetic kidney disease. The aim of this study was to estimate the burden of CKD in patients with diabetes and examine the ability of serum creatinine and albuminuria to detect clinically meaningful CKD compared with estimated glomerular filtration rate (eGFR).
All adults known to have diabetes in primary and secondary care in Salford, UK, alive with independent renal function on 1 January 2004 were included in this observational study (n=7596). Demographic and laboratory parameters were obtained from the Electronic Patient Record. eGFR was determined using the 4-variable modification of diet in renal disease (MDRD) formula. Clinically meaningful CKD was defined as an eGFR <60 ml/min/1.73 m(2).
Creatinine and albuminuria were measured in the preceding 2 years in 82.3 and 55.2% of subjects, respectively. In patients with CKD, normoalbuminuria was present in 48.8%, and serum creatinine was normal (<or=120 micromol/l) in 54.7%. An abnormal serum creatinine (>or=120 micromol/l) had a sensitivity and specificity of 45.3 and 100%, respectively, to identify CKD. The combination of abnormal creatinine and albuminuria had an improved performance but still failed to detect a large number with CKD (sensitivity 82.4%, specificity 75.4%). Serum creatinine failed to identify CKD more often in females (OR 8.22, CI 6.56-10.29).
Undiagnosed CKD is common in diabetes. Current screening strategies, based on creatinine or albuminuria, fail to identify a considerable number of subjects with CKD. Incorporating eGFR into screening for CKD would identify individuals earlier in the natural history of the disease and enable early effective treatment to delay progression of CKD.
[Show abstract][Hide abstract] ABSTRACT: Background and objective: An economic analysis of telemedicine support to improve glycemic control in patients with type 2 diabetes mellitus, illustrating the use of an analytic framework that efficiently combines telemedicine program findings with published estimates of treatment cost effectiveness. Method: The Pro-Active Call Centre Treatment Support (PACCTS) trial compared tailored, protocol-driven call-center support with usual care as methods to manage glycemic control in 591 patients with diabetes in Salford, UK. Economic analysis of the trial describes the cost of delivering telemedicine support and level of improved glycemic control achieved in patients. These findings are linked to current best evidence for the long-term cost effectiveness of treatment to help inform whether the provision of call-center support to improve glycemic control should become routine health policy. Results: Under trial conditions, the cost effectiveness of the PACCTS intervention was estimated to be Lstg 43_400/quality-adjusted life-year (QALY) [2003 costings]. Under routine-use call-center conditions (a full caseload of patients with moderate to poor glycemic control) cost effectiveness was estimated to be lower at Lstg 33_700/QALY. Set against a threshold of Lstg 30_000/QALY, Monte Carlo simulation suggests the probability of PACCTS being cost-effective in routine use is 29%. Discussion: Despite being received well by patients and healthcare professionals alike, telemedicine support solely to achieve improved glycemic control in patients with type 2 diabetes was found to be borderline cost effective. Major uncertainties that could change this result include the underlying cost effectiveness of improved glycemic control, which is currently imprecisely known. Research is ongoing in patients with type 2 diabetes to extend call-center support to improve blood pressure and lipid management, where if similar improvements are obtained, the call center should prove highly cost effective. The novel analytic approach illustrated provides a clear framework for thinking about the design and analysis of behavioral change policies for healthcare.
Disease Management and Health Outcomes 01/2006; 14(6):377-385. · 0.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The dysregulation of the IGF system has been implicated in the pathogenesis of obesity, diabetes, and diabetes complications such as nephropathy, but little is known about the genomics of the IGF system in health and disease. We genotyped 13 single nucleotide polymorphisms (SNPs) in IGFBP1 gene in 732 representative type 2 diabetic patients from the Salford Diabetes Register. Of the 13 SNPs, 8 were polymorphic and 7 of those had minor allele frequencies >0.1, one of which was in the gene promoter and one of which was nonsynonymous in exon 4. The minor alleles of these SNPs and two others were associated with a reduced prevalence of diabetic nephropathy. Haplotype analysis revealed that 97% of the genetic variation for IGFBP1 in the population sample could be accounted for using two of the "reno-protective" SNPs, with other SNPs adding little extra information. One of these two SNPs was the nonsynonymous mutation in exon 4, lying close to the integrin-binding RGD motif, which is thought to affect tissue delivery of IGF-I by IGF-binding protein 1 (IGFBP-1), possibly suggesting a "reno-protective" effect via altered IGFBP-1 binding. In conclusion, we have described the first genomic markers to be associated with diabetic microvascular complications within the human IGFBP1 gene.
[Show abstract][Hide abstract] ABSTRACT: To determine whether Pro-Active Call Center Treatment Support (PACCTS), using trained nonmedical telephonists supported by specially designed software and a diabetes nurse, can effectively improve glycemic control in type 2 diabetes.
A randomized controlled implementation trial of 1-year duration was conducted in Salford, U.K. The trial comprised 591 randomly selected individuals with type 2 diabetes. By random allocation, 197 individuals were assigned to the usual care (control) group and 394 to the PACCTS (intervention) group. Lifestyle advice and drug treatment in both groups followed local guidelines. PACCTS patients were telephoned according to a protocol with the frequency of calls proportional to the last HbA(1c) level. The primary outcome was absolute reduction in HbA(1c), and the secondary outcome was the proportion of patients reducing HbA(1c) by at least 1%.
A total of 332 patients (84%) in the PACCTS group and 176 patients (89%) in the control group completed the study. Final HbA(1c) values were available in 374 patients (95%) in the PACCTS group and 180 patients (92%) in the usual care group. Compared with usual care, HbA(1c) improved by 0.31% (95% CI 0.11-0.52, P = 0.003) overall in the PACCTS patients. For patients with baseline HbA(1c) >7%, the improvement increased to 0.49% (0.21-0.77, P < 0.001), whereas in patients with baseline HbA(1c) <7% there was no change. The difference in the proportions of patients achieving a >/=1% reduction in HbA(1c) significantly favored the PACCTS intervention: 10% (4-16, P < 0.001) overall and 15% (7-24, P < 0.001) for patients with baseline HbA(1c) >7%.
In an urban Caucasian trial population with blood glucose HbA(1c) >7%, PACCTS facilitated significant improvement in glycemic control. Further research should extend the validity of findings to rural communities and other ethnic groups, as well as to smoking and lipid and blood pressure control.
Diabetes Care 03/2005; 28(2):278-82. · 8.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the cost-effectiveness of specialist nurse-led clinics provided to improve lipid and blood pressure control in diabetic patients receiving hospital-based care.
A policy of targeting improved care through specialist nurse-led clinics is evaluated using a novel method, linking the cost-effectiveness of antihypertensive and lipid-lowering treatments with the cost and level of behavioral change achieved by the specialist nurse-led clinics. Treatment cost-effectiveness is modeled from the U.K. Prospective Diabetes Study and Heart Protection Study treatment trials, whereas specialist nurse-led clinics are evaluated using the Specialist Nurse-Led Clinics to Improve Control of Hypertension and Hyperlipidemia in Diabetes (SPLINT) trial.
Good lipid and blood pressure control are cost-effective treatment goals for patients with diabetes. Modeling findings from treatment trials, blood pressure lowering is estimated to be cost saving and life prolonging (-1,400 dollars/quality-adjusted life-year [QALY]), whereas lipid-lowering is estimated to be highly cost-effective (8,230 dollars/QALY). Investing in nurse-led clinics to help achieve these benefits imposes an addition on treatment cost-effectiveness leading to higher estimates: 4,020 dollars/QALY and 19,950 dollars/QALY, respectively. For both clinics combined, the estimated cost-effectiveness is 9,070 dollars/QALY. Using an acceptability threshold of 50,000 dollars/QALY, the likelihood that blood pressure-lowering clinics are cost-effective is 77%, lipid clinics 99%, and combined clinics 83%.
A method is described for evaluating the cost-effectiveness of policies to change patient uptake of health care. Such policies are less attractive than treatment cost-effectiveness (which implies cost-less self-implementation). However, specialist nurse-led clinics, as an adjunct to hospital-based diabetic care, combining both lipid and blood pressure control, appear effective and likely to provide excellent value for money.
Diabetes Care 02/2005; 28(1):40-6. · 8.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are two key methods in which fat intake may be manipulated; the 'substitution model' and the 'reduction model'. However insufficient information is known about the mechanisms of dietary fat reduction in individuals who have successfully reduced their fat intake, to be clear as to which strategy offers the greatest chance of success. Our objective was to ascertain the most effective dietary intervention for improving cardiovascular risk profile. Eighty female volunteers (high fat consumers) were recruited. Each subject was randomly allocated into one of the following groups. Substitution of high-fat foods was made with reduced-fat products, by the reduction of high-fat foods, by a combination of substitution and reduction strategies, or no advice was given. Each intervention lasted 3 months. Anthropometric measures and fasting blood samples were taken at baseline and follow-up. The substitution intervention resulted in weight loss (mean -1.4 (95 % CI -2.4, -0.2) kg) and reduced percentage body fat (mean -1.3 (95% CI -2.0, -0.5)%). There was no significant weight change with the other interventions. Fasting triacylglycerols (-0.2 (SEM 0.07) mm; P=0.04), cholesterol and C-reactive protein (CRP) levels (0.8 (SEM 0.2) mg/l; P=0.04) fell with the substitution intervention, but not with the other interventions. Insulin-like growth factor-1 increased with both substitution and reduction (P=0.02). There was no significant change in fasting insulin or glucose with any intervention. The substitution model of dietary intervention is effective even over a relatively short interval of time in reducing fasting total cholesterol, triacylglycerols and CRP. Although the group size for the present study was small and involved females only, it has significant implications for population intervention strategies.
British Journal Of Nutrition 12/2004; 92(5):809-18. · 3.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The vasculoprotective effects of hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) correlate with cholesterol lowering. HMG-CoA reductase inhibitors also disrupt cellular processes by the depletion of isoprenoids and dolichol. Insulin and insulin-like growth factor (IGF) signaling appear particularly prone to such disruption as intracellular receptor processing requires dolichol for correct N-glycosylation, whereas downstream signaling through Ras requires the appropriate prenylation (farnesol). We determined how HMG-CoA reductase inhibition affected the mitogenic effects of IGF-I and metabolic actions of insulin in 3T3-L1 cells and examined the respective roles of receptor glycosylation and Ras prenylation. IGF-I- and insulin-induced proliferation was significantly reduced by all statins tested, although cerivastatin (10 nm) had the greatest effect (p < 0.005). Although inhibitors of Ras prenylation induced similar results (10 microm FTI-277 89% +/- 7.4%, p < 0.01), the effect of HMG-CoA reductase inhibition could only be partially reversed by farnesyl pyrophosphate refeeding. Treatment with statins resulted in decreased membrane expression of receptors and accumulation of proreceptors, suggesting disruption of glycosylation-dependent cleavage. Glycosylation inhibitors inhibited IGF-I-induced proliferation (tunicamycin p < 0.005, castanospermine p < 0.01, deoxymannojirimycin p < 0.01). High concentrations of statin were necessary to impair insulin-mediated glucose uptake (300 nm = 33% +/- 12% p < 0.05), and this process was not effected by farnesyl transferase inhibition. Gycosylation inhibitors mimicked the effect of statin treatment (tunicamycin p < 0.001, castanospermine p < 0.05, deoxymannojirimycin p < 0.05), and there was insulin proreceptor accumulation. These data imply that HMG-CoA reductase inhibitors disrupt IGF-I signaling by combined effects on Ras prenylation and IGF receptor glycosylation, whereas insulin signaling is only affected by disrupted receptor glycosylation.
Journal of Biological Chemistry 10/2004; 279(37):38353-9. · 4.60 Impact Factor