Effect of glargine insulin delivery method (pen device versus vial/syringe) on glycemic control and patient preferences in patients with type 1 and type 2 diabetes.

OBJECTIVE: To evaluate the effects of two different glargine insulin delivery methods (pen device vs. vial/syringe) on glycemic control and patient preferences in a randomized, open-label, crossover, comparative effectiveness study. METHODS: Thirty-one patients discharged from the hospital were recruited for this study. In the hospital, all patients were treated with a basal-bolus insulin regimen. Upon discharge, 21 patients received glargine by pen device for 3 months and were then switched to vial/syringe for the next 3 months (group 1). Group 2 consisted of 10 patients discharged on vial/syringe and converted to pen device after 3 months. Hemoglobin A1c (HbA1c) was measured at enrollment and at 3 and 6 months. A questionnaire assessing patient preference was administered at 3 and 6 months. RESULTS: Groups 1 and 2 had similar baseline HbA1c (10.7 ± 2.2% and 11.2 ± 2.5%, respectively) and similar reduction in HbA1c at 3 months (7.8 ± 1.7% and 7.3 ± 1.4%, respectively; P<.001 vs. baseline). However, after crossover, the changes in HbA1c from 3 to 6 months were significantly different between groups. HbA1c increased to 8.5 ± 2.0% at 6 months in group 1 after switching to the vial/syringe but remained unchanged (7.1 ± 1.6%) in group 2 after switching to a pen device (P<.01, group 1 vs. group 2). Patient questionnaires after each phase of the trial revealed that patients found the pen device more convenient and were more likely to recommend this insulin delivery method to someone else. CONCLUSION: Patients switching to a glargine pen device achieved lower HbA1c at the 6-month follow-up. Patients in both groups overwhelmingly preferred glargine pens over vials/syringes.

Diabetes and cardiovascular disease: changing the focus from glycemic control to improving long-term survival.

Diabetes mellitus (DM) is the fifth-leading cause of death worldwide and contributes to leading causes of death, cancer and cardiovascular disease, including CAD, stroke, peripheral vascular disease, and other vascular disease. While glycemic management remains a cornerstone of DM care, the co-management of hypertension, atherosclerosis, cardiovascular risk reduction, and prevention of long-term consequences associated with DM are now well recognized as essential to improve long-term survival. Clinical trial evidence substantiates the importance of glycemic control, low-density cholesterol-lowering therapy, blood pressure lowering, control of albuminuria, and comprehensive approaches targeting multiple risk factors to reduce cardiovascular risk. This article presents a review of the role of DM in the pathogenesis of atherosclerosis and cardiac dysfunction, recent evidence on the degree of glycemic control and mortality, and available evidence for a multifaceted approach to improve long-term outcomes for patients.

Cardiovascular disease in diabetes: where does glucose fit in?

CONTEXT: Recent prospective clinical trials have failed to confirm a unique benefit from normalization of glycemia on cardiovascular disease outcomes, despite evidence from basic vascular biology, epidemiological, and cohort studies. EVIDENCE ACQUISITION: The literature was searched using the http://www.ncbi.nlm.nih.gov search engine including over 20 million citations on MEDLINE (1970 to present). Keyword searches included: atherosclerosis, cardiovascular, and glucose. Epidemiological, cohort, and interventional data on cardiovascular disease outcomes and glycemic control were reviewed along with analysis of recent reviews on this topic. EVIDENCE SYNTHESIS: High glucose activates a proatherogenic phenotype in all cell types in the vessel wall including endothelial cells, vascular smooth muscle cells, inflammatory cells, fibroblasts, and platelets, leading to a feedforward atherogenic response. EPIDEMIOLOGICAL AND COHORT STUDIES: Epidemiological and cohort evidence indicates a clear and consistent correlation of glycemia with cardiovascular disease. A recent report of over 25,000 subjects with diabetes in the Swedish National Diabetes Registry verifies this relationship in contemporary practice. Interventional Studies: Prospective randomized interventions targeting a hemoglobin A1c of 6-6.5% for cardiovascular disease prevention failed to consistently decrease cardiovascular events or all-cause mortality. CONCLUSIONS: Basic vascular biology data plus epidemiological and cohort evidence would predict that glucose control should impact cardiovascular events. Prospective clinical trials demonstrate that current strategies that improve blood glucose do not achieve this goal but suggest that a period of optimal control may confer long-term cardiovascular disease benefit. Clinicians should target a hemoglobin A1c of 7% for the prevention of microvascular complications, individualized to avoid hypoglycemia.

Insulin attenuates vascular smooth muscle calcification but increases vascular smooth muscle cell phosphate transport.

Medial artery vascular smooth muscle cell (VSMC) calcification increases the risk of cardiovascular mortality in type 2 diabetes. However, the influence of insulin on VSMC calcification is unclear. We explored the effects of insulin on rat VSMC calcification in vitro and found that in a dose-dependent fashion, insulin attenuates VSMC calcification induced by high phosphate conditions as quantified by the o-cresolphthalein calcium (OCPC) method. In an in vitro model of insulin resistance in which cells are exposed to elevated insulin concentrations and the PI 3-kinase pathway is selectively inhibited, increased VSMC calcification was observed, suggesting that the PI 3-kinase pathway is involved in this attenuating effect of insulin. We postulated that insulin may also have an effect on phosphate or calcium transport in VSMC. We found that insulin increases phosphate transport at 3 and 24 h. This effect was mediated by increased Vmax for phosphate transport but not Km. Because type III sodium-phosphate co-transporters Pit-1 and Pit-2 are found in VSMC, we examined their expression by Western blot and real-time RT-PCR. Insulin stimulates Pit-1 mRNA modestly (*p<0.01 versus control), an effect inhibited by PD98059 but not by wortmannin. Pit-1 protein expression is induced by insulin, an effect also inhibited by PD98059 (*p<0.001 versus insulin alone). Our results suggest a role for insulin in attenuating VSMC calcification which may be disrupted in selective insulin signaling impairment seen in insulin resistance. This effect of insulin contrasts with its effect to induce phosphate transport in VSMC.

Early growth response gene-1 expression in vascular smooth muscle cells effects of insulin and oxidant stress.

BACKGROUND: Cardiovascular mortality is increased in individuals with insulin resistance, and increased oxidant stress is strongly implicated in atherogenesis. Early growth response gene-1 (Egr-1) may be an important link between insulin resistance and oxidant stress. In this study we examined the effects of insulin and oxidant stress on Egr-1 expression in vascular smooth muscle cells (VSMC), and identified mechanisms for these effects on Egr-1. METHODS: Rat VSMC were used to obtain time course and dose-response curves for insulin and oxidant stress on Egr-1 protein expression. Intracellular signaling pathway inhibitors and adenoviral vectors with dominant negative effects on specific signaling pathways were used to determine mechanisms for these effects. RESULTS: Insulin and oxidant stress each significantly stimulate Egr-1 protein expression. Insulin and oxidant stress combined have a greater effect on Egr-1 than either alone. Insulin effects are mediated via the ERK1/2 MAP kinase pathway, whereas oxidant stress effects may be mediated via the ERK5 and p38 MAP kinase pathways. CONCLUSIONS: We demonstrated that insulin and oxidant stress stimulate Egr-1 expression in VSMC. Insulin effects are mediated via the ERK1/2 MAP kinase pathway, whereas oxidant stress effects may be mediated via the ERK5 and p38 MAP kinase pathways. As insulin resistance is characterized by compensatory hyperinsulinemia and selective impairment of the PI 3-kinase pathway with intact signaling along the ERK1/2 MAP kinase pathway, this may have implications for accelerated atherosclerosis in insulin resistance.

Molecular mechanisms of insulin resistance that impact cardiovascular biology.

Insulin resistance is concomitant with type 2 diabetes, obesity, hypertension, and other features of the metabolic syndrome. Because insulin resistance is associated with cardiovascular disease, both scientists and physicians have taken great interest in this disorder. Insulin resistance is associated with compensatory hyperinsulinemia, but individual contributions of either of these two conditions remain incompletely understood and a subject of intense investigation. One possibility is that in an attempt to overcome the inhibition within the metabolic insulin-signaling pathway, hyperinsulinemia may continue to stimulate the mitogenic insulin-signaling pathway, thus exerting its detrimental influence. Here we discuss some of the effects of insulin resistance and mechanisms of potentially detrimental influence of hyperinsulinemia in the presence of metabolic insulin resistance.

Insulin affects vascular smooth muscle cell phenotype and migration via distinct signaling pathways.

Insulin maintains vascular smooth muscle cell (VSMC) quiescence yet can also promote VSMC migration. The mechanisms by which insulin exerts these contrasting effects were examined using alpha-smooth muscle actin (alpha-SMA) as a marker of VSMC phenotype because alpha-SMA is highly expressed in quiescent but not migratory VSMC. Insulin alone maintained VSMC quiescence and modestly stimulated VSMC migration. Wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, decreased insulin-stimulated expression of alpha-SMA mRNA by 26% and protein by 48% but had no effect on VSMC migration. PD98059, a mitogen-activated protein kinase (MAPK) kinase inhibitor, decreased insulin-induced VSMC migration by 52% but did not affect alpha-SMA levels. Platelet-derived growth factor (PDGF) promoted dedifferentiation of VSMC, and insulin counteracted this effect. Furthermore, insulin increased alpha-SMA mRNA and protein levels to 111 and 118%, respectively, after PDGF-induced dedifferentiation, an effect inhibited by wortmannin. In conclusion, insulin's ability to maintain VSMC quiescence and reverse the dedifferentiating influence of PDGF is mediated via the PI3K pathway, whereas insulin promotes VSMC migration via the MAPK pathway. Thus, with impaired PI 3-kinase signaling and intact MAPK signaling, as seen in insulin resistance, insulin may lose its ability to maintain VSMC quiescence and instead promote VSMC migration.