Metformin Safety in the Management of Gestational Diabetes

ObjectiveThe use of metformin in pregnant women is still controversial, despite the increasing reports on metformin’s safety and effectiveness. We aimed to evaluate the maternal and neonatal safety of metformin in subjects with gestational diabetes mellitus (GDM).MethodsWe retrospectively reviewed the clinical records of 186 pregnancies complicated with GDM surveilled at Hospital de Santa Maria, Lisboa, between 2011 and 2012. The maternal and neonatal outcomes of 32 females who took metformin during pregnancy were compared with 121 females controlled with diet and 33 insulintreated females.ResultsOf the 186 GDM subjects, 32 (17.2%) received metformin during pregnancy. No statistical differences between the diet and metformin groups were found with regard to the rates of abortion, prematurity, preeclampsia, macrosomy, small-for-gestational-age (SGA) or largefor- gestational-age (LGA) newborns, cesarean deliveries, neonatal intensive care unit (NICU) admissions, and birth malformations or neonatal injuries. Similarly, there were no differences between the metformin and insulin groups with regard to the referred outcomes. No abortions or perinatal deaths were recorded in the metformin group. Ten out of 32 metformin patients required additional insulin.ConclusionThis retrospective study suggests that metformin is a safe alternative or additional treatment to insulin in females with GDM. Metformin was not associated with a higher risk of maternal or neonatal complications when compared to the insulin or diet groups. (Endocr Pract. 2014;20:1022-1031)     

Managing Diabetes During Pregnancy with Insulin Lispro: A Safe Alternative to Human Insulin

ObjectiveTo assess the safety of the use of insulin lispro during pregnancy on the basis of published literature and to report on any related efficacy findings.MethodsThe National Center for Biotechnology Information Entrez Database PubMed (http://www.ncbi. nlm.nih.gov/pubmed/) was used to search for citations from MEDLINE in the November 2009 time frame that contained safety data and efficacy results on the use of insulin lispro during pregnancy.ResultsFrom the MEDLINE search, we identified a total of 27 publications (with 1, 265 pregnancies) with relevant information, which were included in this report. No statistically significant differences in the rates of occurrence of congenital anomalies or spontaneous abortions associated with the use of insulin lispro during pregnancy, in comparison with the use of human insulin, were reported. Moreover, in comparison with human insulin, insulin lispro was reported to result in improved glycemic control, as demonstrated by lower postprandial glucose concentrations and hemoglobin A1c levels.ConclusionThe current review of the published literature indicates that insulin lispro is a safe alternative to human insulin with similar perinatal outcomes and potentially improved glycemic control in the management of diabetes during pregnancy. (Endocr Pract. 2010;16: 1020-1027)     

Graves Hyperthyroidism and Pregnancy: A Clinical Update

ObjectiveTo provide a clinical update on Graves’ hyperthyroidism and pregnancy with a focus on treatment with antithyroid drugs.MethodsWe searched the English-language literature for studies published between 1929 and 2009 related to management of hyperthyroidism in pregnancy. In this review, we discuss differential diagnosis of hyperthyroidism, management, importance of early diagnosis, and importance of achieving proper control to avoid maternal and fetal complications.ResultsDiagnosing hyperthyroidism during pregnancy can be challenging because many of the signs and symptoms are similar to normal physiologic changes that occur in pregnancy. Patients with Graves disease require prompt treatment with antithyroid drugs and should undergo frequent monitoring for signs of fetal and maternal hyperthyroidism and hypothyroidism. Rates of maternal and perinatal complications are directly related to control of hyperthyroidism in the mother. Thyroid receptor antibodies should be assessed in all women with hyperthyroidism to help predict and reduce the risk of fetal or neonatal hyperthyroidism or hypothyroidism. The maternal thyroxine level should be kept in the upper third of the reference range or just above normal, using the lowest possible antithyroid drug dosage. Hyperthyroidism may recurin the postpartum period as Graves disease or postpartum thyroiditis; thus, it is prudent to evaluate thyroid function 6 weeks after delivery. Preconception counseling, a multidisciplinary approach to care, and patient education regarding potential maternal and fetal complications that can occur with different types of treatment are important.ConclusionPreconception counseling and a multifaceted approach to care by the endocrinologist and the obstetric team are imperative for a successful pregnancy in women with Graves hyperthyroidism. (Endocr Pract. 2010;16:118-129)     

Hypothyroxinemia and Pregnancy

ObjectiveTo evaluate the peer-reviewed literature on iodine deficiency and hypothyroxinemia in pregnancy.MethodsWe review published studies on isolated hypothyroxinemia in pregnancy, methodology of free thyroxine (T₄) assays, impact of iodine deficiency on free T₄ levels, and status of ongoing prospective randomized trials of isolated hypothyroxinemia during pregnancy.ResultsHypothyroxinemia during pregnancy is common. Studies have demonstrated the pivotal role exerted by maternal T₄ on fetal brain development and the negative impact of hypothyroxinemia on neurobehavioral performance in offspring. Two intervention studies have demonstrated a positive effect on neurodevelopment in children of mothers promptly supplemented with iodine compared with the neurodevelopment in children of nonsupplemented mothers. Free T₄ assays presently in clinical use have limitations. Preliminary results of the Controlled Antenatal Thyroid Study (CATS) are somewhat mixed, and the National Institutes of Health Maternal Fetal Medicine Thyrotropin Study (TSH Study) will be completed in 2015. Knowledge regarding the impact of isolated hypothyroxinemia has progressed, but major questions remain. An optimal diagnostic test for free T₄ during pregnancy (accurate, inexpensive, and widely available) remains elusive. Trimester-specific normative data and normal ranges from different geographic regions do not exist.ConclusionsData published to date are insufficient to recommend levothyroxine therapy in pregnant women with isolated hypothyroxinemia. Adequate iodine intake should be recommended before conception and early in pregnancy. (Endocr Pract. 2011;17:422-429)     

Does Use of Low-Molecular-Weight Heparin during Pregnancy Influence the Risk of Prolonged Labor: A Population-Based Cohort Study

BackgroundThe use of low-molecular-weight heparins (LMWHs) during pregnancy is increasing. In vitro studies and small clinical studies support the hypothesis that LMWH treatment during pregnancy may reduce duration of labor. The aim of this study was to investigate if use of LMWH is associated with a reduced risk of diagnosis of prolonged labor, after taking maternal, fetal and other delivery characteristics into account.ConclusionsTreatment with LMWH during pregnancy is not associated with a risk of diagnosis of prolonged labor after adjustments for maternal, fetal and delivery characteristics.     

Seguridad de los análogos de insulina: qué evaluar,cómo hacerlo y cómo interpretar los resultados

The widespread use of insulin analogues is based not only on the pharmacokinetics of these preparations, which is much closer to the physiology of insulin secretion under normal conditions, but also on their safety and effectiveness. The publication of a possible association between the use of a long-acting insulin analogue (glargine) and breast cancer has caused uneasiness among the medical community regarding the safety of these analogues.The mechanism of increased tumor activity of insulin analogues is explained by the fact that they act through insulin receptors (IR) and insulin-like growth factor-1 (IGF-1R), stimulating cell growth and inhibiting apoptosis. There are two major mechanisms: an increase in the binding time of insulin to IR and increased activation of IGF-1R. Therefore, to evaluate the safety of an analogue, the slower dissociation rate from its insulin receptor must be excluded, as well as the increased affinity for the IGF-1 receptor. This is equivalent to an index of mitogenic/metabolic activity of less than 1. These aspects can only be evaluated through study of cell lines and animal testing, which are reductionist models that cannot always be extrapolated to humans. To date, there are no data to question the safety of insulin analogues in general. However, the results of observational studies and some in vitro studies, suggesting a potential risk of mitogenicity with the administration of glargine, have caused some alarm among the medical community. Until now, there are no data to refute or confirm this risk and, therefore, evaluation of the existing data is crucial to obtain objective information.     

Glycemic Variation and Hypoglycemia in Patients with well-Controlled Type 1 Diabetes on a Multiple Daily Insulin Injection Program with use of Glargine and Ultralente as Basal Insulin

ObjectiveTo evaluate glycemic variation and hypo-glycemia in patients with well-controlled type 1 diabetes receiving multiple daily insulin injections during glargine and Ultralente use as basal insulin in a clinical trial.MethodsTwenty-two patients (12 men and 10 women, median age, 43 years), with a hemoglobin A1c level < 7.8%, were randomized in a crossover design to receive either insulin glargine or Ultralente insulin as basal insulin for 4 months each, with insulin aspart as prandial insulin. Continuous glucose monitoring and the Fear of Hypoglycemia questionnaire were used at baseline and at the end of each treatment period.ResultsWhereas the mean amplitude of glycemic excursions showed a correlation with the area under the curve of blood glucose < 3.89 mmol/L per day, the number of periods during the day with hypoglycemia was significantly correlated with the M value. Measures of glycemic variation did not differ significantly between glargine and Ultralente treatment. With use of glargine therapy, the SD of blood glucose levels showed a tendency to be lower and the SD of nocturnal blood glucose concentrations was significantly lower. Glucose concentrations were significantly lower during the 1 hour before and the 3 hours after lunch with use of Ultralente. The “Worry” scale on the Fear of Hypoglycemia questionnaire was less during Ultralente therapy and correlated with the number of times blood glucose concentrations were < 3.89 mmol/L daily.ConclusionMeasures of glycemic variability and hypoglycemia need to be studied more in clinical trials of glycemic control in patients with type 1 diabetes. Glycemic variability is less, particularly at night, with glargine as basal insulin. (Endocr Pract. 2007;13:244-250)     

Placental Glucose Transfer: A Human In Vivo Study

ObjectivesThe placental transfer of nutrients is influenced by maternal metabolic state, placenta function and fetal demands. Human in vivo studies of this interplay are scarce and challenging. We aimed to establish a method to study placental nutrient transfer in humans. Focusing on glucose, we tested a hypothesis that maternal glucose concentrations and uteroplacental arterio-venous difference (reflecting maternal supply) determines the fetal venous-arterial glucose difference (reflecting fetal consumption).MethodsCross-sectional in vivo study of 40 healthy women with uncomplicated term pregnancies undergoing planned caesarean section. Glucose and insulin were measured in plasma from maternal and fetal sides of the placenta, at the incoming (radial artery and umbilical vein) and outgoing vessels (uterine vein and umbilical artery).ResultsThere were significant mean (SD) uteroplacental arterio-venous 0.29 (0.23) mmol/L and fetal venous-arterial 0.38 (0.31) mmol/L glucose differences. The transplacental maternal-fetal glucose gradient was 1.22 (0.42) mmol/L. The maternal arterial glucose concentration was correlated to the fetal venous glucose concentration (r = 0.86, p<0.001), but not to the fetal venous-arterial glucose difference. The uteroplacental arterio-venous glucose difference was neither correlated to the level of glucose in the umbilical vein, nor fetal venous-arterial glucose difference. The maternal-fetal gradient was correlated to fetal venous-arterial glucose difference (r = 0.8, p<0.001) and the glucose concentration in the umbilical artery (r = −0.45, p = 0.004). Glucose and insulin concentrations were correlated in the mother (r = 0.52, p = 0.001), but not significantly in the fetus. We found no significant correlation between maternal and fetal insulin values.ConclusionsWe did not find a relation between indicators of maternal glucose supply and the fetal venous-arterial glucose difference. Our findings indicate that the maternal-fetal glucose gradient is significantly influenced by the fetal venous-arterial difference and not merely dependent on maternal glucose concentration or the arterio-venous difference on the maternal side of the placenta.     

Once-Daily Insulin Glargine Versus 6-Hour Sliding Scale Regular Insulin for Control of Hyperglycemia after a Bariatric Surgical Procedure: A Randomized Clinical Trial

ObjectiveTo determine whether once-daily insulin glargine could provide better glycemic control after an abdominal surgical procedure than the traditional use of sliding scale regular insulin (SSRI).MethodsBecause 20% to 30% of patients undergoing gastric bypass have a history of overt diabetes and another 5% to 10% are estimated to have impaired glucose tolerance, we chose to study these patients. We treated 81 patients with postoperative blood glucose levels of more than 144 mg/dL after a Roux-en-Y gastric bypass surgical procedure. They were randomized to receive either SSRI or insulin glargine either directly or after initial intravenous insulin infusion in the intensive care unit (ICU).ResultsOverall, the mean blood glucose level after SSRI therapy was 154 ± 33 mg/dL, and the mean blood glucose value after insulin glargine treatment was 134 ± 30 mg/dL (P < 0.01). The mean blood glucose level for patients first treated with intravenous insulin infusion in the ICU was 125 mg/dL, in comparison with 145 mg/dL in the non-ICU patients whose treatment began directly with 0.3 U/kg of insulin glargine. Of 926 blood glucose measurements, only 3 were less than 60 mg/dL.ConclusionIn this study, control of postoperative hyperglycemia was significantly better with use of insulin glargine in comparison with SSRI therapy, and hypo-glycemia was very infrequent. (Endocr Pract. 2007;13: 225-231)     

A Retrospective Study Comparing Neutral Protamine Hagedorn Insulin With Glargine As Basal Therapy In Prednisone-Associated Diabetes Mellitus In Hospitalized Patients

ObjectiveTo compare glycemic outcomes in hospitalized patients with or without type 2 diabetes mellitus receiving neutral protamine Hagedorn insulin (NPH) vs glargine as basal insulin for management of glucocorticoid-associated hyperglycemia.MethodsWe conducted a retrospective review of electronic medical records in prednisone-treated adult patients with hyperglycemia in a university hospital. Consecutive patients were selected in both the NPH and glargine cohorts using inclusion and exclusion criteria. Baseline characteristics were assessed in each cohort. Glycemic outcomes were analyzed by comparing fasting blood glucose, mean daily blood glucose concentration, median daily blood glucose concentration, and the number of hypoglycemic episodes on a prespecified index day.ResultsOne hundred twenty patients were included: 60 patients in the NPH cohort and 60 patients in the glargine cohort. The weight-based insulin requirement was lower in the NPH cohort than in the glargine cohort (0.27 ± 0.2 units/kg vs 0.34 ± 0.2 units/kg [P = .04] for basal insulin and 0.26 ± 0.2 units/kg vs 0.36 ± 0.2 units/kg [P = .03] for bolus insulin). NPH and glargine cohorts were similar regarding age, sex, race, body mass index, hemoglobin A_1c, serum creatinine, and prednisone dosage. Glycemic outcomes in the NPH cohort compared with outcomes in the glargine cohort were similar regarding mean fasting blood glucose concentration (134 ± 49 mg/dL vs 139 ± 54 mg/dL [P = .63]), mean daily blood glucose (167 ± 46 mg/dL vs 165 ± 52 mg/dL [P = .79]), median blood glucose (160 ± 49 mg/dL vs 159 ± 57 mg/dL [P = .90]), and number of hypoglycemic episodes per day (0.12 ± 0.3 vs 0.10 ± 0.3 [P = .77]).ConclusionsNPH and glargine appear to be equally effective as basal insulin in the management of hyperglycemia in hospitalized patients receiving prednisone. However, the total daily insulin doses used were lower in the NPH cohort. (Endocr Pract. 2012;18:712-719)     

Thyroid Function And 3, 3'-Diiodothyronine Sulfate Cross-Reactive Substance (Compound W) in Maternal Hyperthyroidism With Antithyroid Treatment

ObjectiveTo test whether the serial measurement of maternal levels of compound W, a 3, 3′-diiodothyronine sulfate cross-reactive substance, can serve as a potential indicator of fetal thyroid function in pregnant women receiving antithyroid medication.MethodsCompound W was measured repeatedly in serum of pregnant women with hyperthyroidism treated with antithyroid medication. Free thyroxine levels of mothers and serum thyroid-stimulating hormone levels of 1-day-old neonates were analyzed by local clinical or state laboratories.ResultsUse of minimal antithyroid medication impaired the progressive increase of compound W seen in euthyroid mothers during pregnancy. At term, depressed compound W levels in maternal serum were found in 7 of 22 pregnancies; in 1 case, maternal compound W was suppressed and newborn thyroid-stimulating hormone was elevated. Seven mothers with treated hyperthyroidism failed to show an increase in serum levels of compound W after midterm.ConclusionNormal progression of maternal serum compound W may be an index of normal fetal thyroid development in mothers with hyperthyroidism treated with necessary antithyroid medication. (Endocr Pract. 2011;17:170-176)     

Real-World Insulin Treatment Persistence among Patients with Type 2 Diabetes

ObjectiveTo evaluate real-world treatment persistence among patients with type 2 diabetes mellitus (T2DM) initiating treatment with insulin.MethodsPatient-level data were pooled from 3 previously published observational retrospective studies evaluating patients with T2DM who were previously on oral antidiabetic drugs (OADs) and initiated with a basal analog insulin (insulin glargine or insulin detemir). Treatment persistence was defined as remaining on the study drug during the 1-year follow-up period without discontinuation or switching after study drug initiation. Analyses were conducted to identify baseline factors associated with persistence with insulin therapy and to estimate the association between insulin treatment persistence and patients’ clinical and economic outcomes during the follow-up period.ResultsA total of 4,804 patients with T2DM (insulin glargine: n = 4,172, insulin detemir: n = 632) were included. The average insulin persistence rate over the 1-year follow-up period was 65.0%. A significantly higher persistence rate was associated with older age, initiation with insulin glargine using either disposable pens or vial-and-syringe, and with baseline exenatide or sitagliptin use. Higher insulin treatment persistence was also associated with lower hemoglobin A_1c (A1C) at follow-up, a greater reduction in A1C from baseline, and lower health care utilization.ConclusionIn real-world settings, treatment persistence among patients with T2DM initiating basal insulin is influenced by the type of insulin and patient factors. Greater insulin treatment persistence is linked to improved clinical outcomes and reduced health care utilization. (Endocr Pract. 2014;20:52-61)     

A Comparison of Twice-Daily Biphasic Insulin Aspart 70/30 and Once-Daily Insulin Glargine in Persons With Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Therapy: A Randomized,Open-Label Study

ObjectiveTo compare efficacy and safety of biphasic insulin aspart 70/30 (BIAsp 30) with insulin (glargine) in type 2 diabetic patients who were not maintaining glycemic control on basal insulin and oral antidiabetic drugs.MethodsIn a 24-week, open-label, parallel-group trial, type 2 diabetic patients who were not maintaining glycemic control on basal insulin (glargine or neutral protamine Hagedorn) + oral antidiabetic drugs were randomly assigned to twice-daily BIAsp 30 + metformin or oncedaily glargine + metformin + secretagogues (secretagogues were discontinued in the BIAsp 30 arm).ResultsOne hundred thirty-seven patients were randomly assigned to the BIAsp 30 group and 143 patients were randomly assigned to the glargine group. Of 280 patients randomized, 229 (81.8%) completed the study. End-of-trial hemoglobin A_1c reductions were − 1.3% (BIAsp 30) vs − 1.2% (glargine) (treatment difference: 95% confidence interval, − 0.06 [− 0.32 to 0.20]; P = .657). Of patients taking BIAsp 30, 27.3% reached a hemoglobin A_1c level < 7.0% compared with 22.0% of patients taking glargine (treatment difference: P = .388). Glucose increment averaged over 3 meals was lower in the BIAsp 30 arm (treatment difference: − 17.8 mg/dL, P = .001). Fasting plasma glucose reductions from baseline were − 13.8 mg/ dL (BIAsp 30) vs − 42.5 mg/dL (glargine) (P = .0002). Final minor hypoglycemia rate, insulin dose, and weight change were higher in the BIAsp 30 arm (6.5 vs 3.4 events/patient per year, P <.05; 1.19 vs 0.63 U/kg; and 3.1 vs 1.4 kg, P = .0004, respectively).ConclusionsDespite not receiving secretagogues, patients taking BIAsp 30 + metformin achieved similar hemoglobin A_1c levels and lower postprandial plasma glucose compared with those receiving glargine + metformin + secretagogues. The large improvement in the glargine group suggests the patients were not true basal failures at randomization. While switching to BIAsp 30 improves glycemic control in this patient population, remaining on basal insulin and optimizing the dose may be equally effective in the short term. (Endocr Pract. 2011;17:41-50)     

Review on the in vitro interaction of insulin glargine with the insulin/insulin-like growth factor system: potential implications for metabolic and mitogenic activities

Insulin analogues provide clinically important benefits for people with diabetes, including more predictable action profiles and lower risk of hypoglycemia compared with human insulin. However, it has been suggested that certain insulin analogues may lead to greater activation of insulin-like growth factor-1 (IGF-1) signaling, with risk for adverse mitogenic effects. This article aims to critically review studies on the mitogenic effects of the insulin analogue insulin glargine (glargine) and its metabolites. A review of in vitro studies suggests that glargine may stimulate mitogenic activity in some cell lines at supraphysiological concentrations (nanomolar/micromolar concentrations). Mitogenicity appeared to be related to the expression of the IGF-1 receptor, being present in cells expressing high levels of the receptor and absent in cells with limited or no IGF-1 receptor expression. In animal studies, glargine did not promote tumor growth, despite administration at supraphysiological concentrations (nanomolar/micromolar), which are unlikely to be observed in clinical practice because the doses needed to produce these concentrations are liable to lead to hypoglycemia. Furthermore, glargine in vivo is rapidly transformed into its metabolites, the metabolic and mitogenic characteristics of which have been shown to be broadly equal to those of human insulin. Thus, the suggestion of increased relative mitogenic potency of insulin glargine seen in some cell lines does not appear to carry over to the in vivo situation in animals and humans.     

Performance of Polymerase Chain Reaction Analysis of the Amniotic Fluid of Pregnant Women for Diagnosis of Congenital Toxoplasmosis: A Systematic Review and Meta-Analysis

IntroductionCongenital infection caused by Toxoplasma gondii can cause serious damage that can be diagnosed in utero or at birth, although most infants are asymptomatic at birth. Prenatal diagnosis of congenital toxoplasmosis considerably improves the prognosis and outcome for infected infants. For this reason, an assay for the quick, sensitive, and safe diagnosis of fetal toxoplasmosis is desirable.GoalTo systematically review the performance of polymerase chain reaction (PCR) analysis of the amniotic fluid of pregnant women with recent serological toxoplasmosis diagnoses for the diagnosis of fetal toxoplasmosis.MethodA systematic literature review was conducted via a search of electronic databases; the literature included primary studies of the diagnostic accuracy of PCR analysis of amniotic fluid from pregnant women who seroconverted during pregnancy. The PCR test was compared to a gold standard for diagnosis.ResultsA total of 1.269 summaries were obtained from the electronic database and reviewed, and 20 studies, comprising 4.171 samples, met the established inclusion criteria and were included in the review. The following results were obtained: studies about PCR assays for fetal toxoplasmosis are generally susceptible to bias; reports of the tests’ use lack critical information; the protocols varied among studies; the heterogeneity among studies was concentrated in the tests’ sensitivity; there was evidence that the sensitivity of the tests increases with time, as represented by the trimester; and there was more heterogeneity among studies in which there was more time between maternal diagnosis and fetal testing. The sensitivity of the method, if performed up to five weeks after maternal diagnosis, was 87% and specificity was 99%.ConclusionThe global sensitivity heterogeneity of the PCR test in this review was 66.5% (I²). The tests show low evidence of heterogeneity with a sensitivity of 87% and specificity of 99% when performed up to five weeks after maternal diagnosis. The test has a known performance and could be recommended for use up to five weeks after maternal diagnosis, when there is suspicion of fetal toxoplasmosis.     

Quality of Life and Insulin Therapy in Type 2 Diabetes Mellitus

Background: A frequently cited barrier to insulin use in type 2 diabetes mellitus (DM) is concern about the adverse effects on quality of life. Results of studies in this area have been mixed, with insulin use showing decreased, enhanced, or no impact on quality of life.Objective: The purpose of this paper is to discuss the state of the science regarding the effects of insulin on quality of life and to present strategies providers can implement in their clinical practices to decrease barriers to insulin use among patients with type 2 DM.Methods: An English-language MEDLINE search of the current literature using the terms insulin and quality of life was conducted for this article.Results: Although patient-identified concerns regarding insulin use represent some aspects of quality of life, study results have been mixed. However, 2 large studies examining the use of insulin glargine and its effects on quality of life found that glargine was associated with significantly greater improvements in quality of life when added to oral antidiabetic agents (OADs) than was the use of OADs alone. Another study examined the effects of intensive multi- therapy (monthly visits, self-management diabetes education, and medication adjustments) on quality of life among patients with type 2 DM and found that quality-of-life scores improved among patients who initiated insulin therapy during the trial. The effects of insulin delivery systems on quality of life have also been assessed. In these studies, patients preferred insulin pens over vials and syringes and inhaled over injected insulin. Health care providers can facilitate acceptance of insulin by employing strategies to help patients overcome psychological barriers to insulin therapy.Conclusions: Although patient concerns about the effects of insulin use are legitimate, insulin therapy is often needed to achieve treatment targets. Providers can reduce the impact on quality of life by addressing barriers, helping patients improve metabolic control, and providing ongoing information and support.     

Solid Phase Synthesis of an Analogue of Insulin, A0:R glargine, That Exhibits Decreased Mitogenic Activity

Numerous analogues of insulin have been prepared over the past three decades for use in diabetic therapy. However, only two long-acting insulins have been approved for clinical use. One is Levemir (Novo Nordisk) and the other is Lantus (Sanofi-Aventis). Glargine (commercial name: Lantus) is characterized by a substitution of Gly in place of Asn at the C terminus of the A-chain and addition of two Arg residues to the C terminus of the B-chain. Despite the clinical advantages of glargine, it is not without concern that its increased affinity for the IGF-1 receptor may correlate with increased mitogenic activity. Recently, a systematic study of modified analogues of glargine showed that placement of an extra Arg residue at the N terminus of the A-chain conferred improved insulin:IGF-1 receptor selectivity without significant loss of pharmacological profile. However, as it is difficult to prepare such an analogue in high yield by recombinant DNA methods, we undertook its chemical assembly by our refined solid phase synthesis method. We describe herein its chemical preparation and biological activity in both insulin receptor binding assays and DNA synthesis assays. The synthetic analogue, A0:R glargine, showed slightly reduced affinity for IR-B (twofold) compared to native insulin. In stimulating DNA synthesis, A0:R glargine was slightly less potent compared to insulin or glargine. This result ultimately confirms the previous report that A0:R glargine has a lower potency in mitogenic assays compared to glargine. This glargine analogue thus could be a potential lead compound for drug design and development for the treatment of diabetes.