The ongoing evolution of basal insulin therapy over 100 years and its promise for the future.

The evolution of basal insulin therapy over the past 100 years since the discovery of insulin is a testimony to the biomedical bench-to-bedside process, wherein incremental advances in the basic sciences are progressively translated over time into a series of enhancements in clinical care, each building upon the success of its predecessors. The emergence of recombinant DNA technology and the resultant biosynthesis of human insulin in the 1980s provided the critical capacity to bioengineer designer insulin analogues with pharmacokinetic and pharmacodynamic properties that can better mimic, although not fully replicate, the effects of endogenous insulin secretion. Through these efforts, basal insulin therapy has progressed over this time from first-generation analogues (glargine U-100, detemir) to second-generation analogues (glargine U-300, degludec) to ultra-long-acting formulations that are suitable for administration once weekly (icodec). Each iteration in this progression has represented a step closer towards the goal of replicating the continuous secretion of insulin that normally comprises the basal output of the pancreatic beta-cells between meals, during episodes of fasting and overnight. However, it may be that we may have reached the achievable limit in the context of an "open-loop" approach, such that only with the addition of closed loop control will we be able to achieve physiologic basal insulin replacement. In this review, we will examine the evolution of basal insulin therapy over the past 100 years and its implications for patient care and outcomes in current practice and the future.

Metformin for gestational diabetes study: metformin vs insulin in gestational diabetes: glycemic control and obstetrical and perinatal outcomes: randomized prospective trial.

BACKGROUND: Gestational diabetes that is not properly controlled with diet has been commonly treated with insulin. In recent years, several studies have published that metformin can lead to, at least, similar obstetrical and perinatal outcomes as insulin. Nevertheless, not all clinical guidelines endorse its use, and clinical practice is heterogeneous. OBJECTIVE: This study aimed to test whether metformin could achieve the same glycemic control as insulin and similar obstetrical and perinatal results, with a good safety profile, in women with gestational diabetes that is not properly controlled with lifestyle changes. STUDY DESIGN: The metformin for gestational diabetes study was a multicenter, open-label, parallel arms, randomized clinical trial performed at 2 hospitals in Málaga (Spain), enrolling women with gestational diabetes who needed pharmacologic treatment. Women at the age of 18 to 45 years, in the second or third trimesters of pregnancy, were randomized to receive metformin or insulin (detemir or aspart). The main outcomes were (1) glycemic control (mean glycemia, preprandial and postprandial) and hypoglycemic episodes and (2) obstetrical and perinatal outcomes and complications (hypertensive disorders, type of labor, prematurity, macrosomia, large for gestational age, neonatal care unit admissions, respiratory distress syndrome, hypoglycemia, jaundice). Outcomes were analyzed on an intention-to-treat basis. RESULTS: Between October 2016 and June 2019, 200 women were randomized, 100 to the insulin-treated group and 100 to the metformin-treated group. Mean fasting and postprandial glycemia did not differ between groups, but postprandial glycemia was significantly better after lunch or dinner in the metformin-treated-group. Hypoglycemic episodes were significantly more common in the insulin-treated group (55.9% vs 17.7% on metformin; odds ratio, 6.118; 95% confidence interval, 3.134-11.944; P=.000). Women treated with metformin gained less weight from the enrollment to the prepartum visit (36-37 gestational weeks) (1.35±3.21 vs 3.87±3.50 kg; P=.000). Labor inductions (45.7% [metformin] vs 62.5% [insulin]; odds ratio, 0.506; 95% confidence interval, 0.283-0.903; P=.029) and cesarean deliveries (27.6% [metformin] vs 52.6% [insulin]; odds ratio, 0.345; 95% confidence interval, 0.187-0.625; P=.001) were significantly lower in the metformin-treated group. Mean birthweight, macrosomia, and large for gestational age and babies' complications were not different between treatment groups. The lower cesarean delivery rate for women treated with metformin was not associated with macrosomia, large or small for gestational age, or other complications of pregnancy. CONCLUSION: Metformin treatment was associated with a better postprandial glycemic control than insulin for some meals, a lower risk of hypoglycemic episodes, less maternal weight gain, and a low rate of failure as an isolated treatment. Most obstetrical and perinatal outcomes were similar between groups.

Investigations of Albumin-Insulin Detemir Complexes Using Molecular Dynamics Simulations and Free Energy Calculations.

Insulin detemir is a lipidated insulin analogue that obtains a half-life extension by oligomerization and reversible binding to human serum albumin. In the present study, the complex between a detemir hexamer and albumin is investigated by an integrative approach combining molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, and dynamic light scattering (DLS) experiments. Recent reported small-angle X-ray scattering data could not unambiguously resolve the exact binding site of detemir on albumin. We therefore applied MD simulations to deduce the binding site and key protein-protein interactions. MD simulations were started from initial complex structures based on the SAXS models, and free energies of binding were estimated from the simulations by using the MM-PBSA approach for the different binding positions. The results suggest that the overlapping FA3-FA4 binding site (named FA4) is the most favorable site with a calculated free energy of binding of -28 ± 6 kcal/mol and a good fit to the reported SAXS data throughout the simulations. Multiple salt bridges, hydrogen bonds, and favorable van der Waals interactions are observed in the binding interface that promote complexation. The binding to FA4 is further supported by DLS competition experiments with the prototypical FA4 ligand, ibuprofen, showing displacement of detemir by ibuprofen. This study provides information on albumin-detemir binding on a molecular level, which could be utilized in a rational design of future lipidated albumin-binding peptides.

The rate of hyperglycemia and ketosis with insulin degludec-based treatment compared with insulin detemir in pediatric patients with type 1 diabetes: An analysis of data from two randomized trials.

BACKGROUND: Historically, data on the rate of hyperglycemia and ketosis have not been collected in clinical trials. However, it is clinically important to assess the rate of these events in children with type 1 diabetes (T1D). This question was addressed in two pediatric trials using insulin degludec (degludec). OBJECTIVE: To assess the rate of hyperglycemia and ketosis in two-phase 3b trials investigating degludec (Study 1) and degludec with insulin aspart (IDegAsp [Study 2]) vs insulin detemir (IDet). SUBJECTS: Patients (aged 1-17 years inclusive) with T1D treated with insulin for ≥3 months. METHODS: Study 1: patients were randomized to degludec once daily (OD) or IDet OD/twice daily (BID) for 26 weeks, followed by a 26-week extension phase. Study 2: patients were randomized to IDegAsp OD or IDet OD/BID for 16 weeks. Bolus mealtime IAsp was included in both studies. In Study 1, hyperglycemia was recorded if plasma glucose (PG) was >11.1 mmol/L, with ketone measurement required with significant hyperglycemia (>14.0 mmol/L). In Study 2, hyperglycemia was recorded with PG >14.0 mmol/L where the subject looked/felt ill, with ketone measurement also required in these hyperglycemic patients. In this post hoc analysis, the hyperglycemia threshold was 14.0 mmol/L for uniformity. RESULTS: Despite similar rates of hyperglycemia with degludec/IDegAsp compared with IDet, the rates of ketosis were lower with degludec/IDegAsp. CONCLUSIONS: These trials, the first to systematically collect data on ketosis in pediatric patients with T1D, demonstrate the potential of degludec/IDegAsp to reduce rates of metabolic decompensation, compared with IDet.

Efficacy and safety of a fixed combination of insulin degludec/insulin aspart in children and adolescents with type 1 diabetes: A randomized trial.

BACKGROUND: Insulin degludec/insulin aspart (IDegAsp) is a fixed soluble co-formulation of basal and bolus insulin. OBJECTIVE: To evaluate efficacy and safety of IDegAsp in pediatric patients with type 1 diabetes (T1D). SUBJECTS: Children and adolescents (aged 1 to <18 years) with T1D. METHODS: A 16-week, phase 3b, treat-to-target, parallel-group, open-label, non-inferiority trial was conducted at 63 sites in 14 countries from October 2013 to November 2014. Patients were randomized 1:1 (age stratified: 1-<6 years; 6-<12 years; 12-<18 years) to IDegAsp once daily (OD) plus insulin aspart (IAsp) for remaining meals (IDegAsp + IAsp), or IDet OD or twice daily plus mealtime IAsp (IDet + IAsp). The primary end-point was HbA1c change from baseline at week 16. RESULTS: A total of 362 participants were randomized to IDegAsp + IAsp (n = 182) or IDet + IAsp (n = 180). HbA1c decreased from baseline to week 16 by 0.3% in both groups (estimated treatment difference: -0.04%-points [-0.23; 0.15]95%CI (-0.45 mmol/mol [-2.51; 1.60]95%CI ), confirming non-inferiority. There were no significant differences between treatment groups in fasting or self-measured plasma glucose. Confirmed hypoglycemia rates did not significantly differ between groups. There was a significant reduction in basal and total insulin dose with IDegAsp + IAsp vs IDet + IAsp (post hoc analysis). Mean number of injections/day was 3.6 and 4.9 with IDegAsp + IAsp and IDet + IAsp, respectively (post hoc analysis). A non-significant higher rate of severe hypoglycemia was observed with IDegAsp + IAsp vs IDet + IAsp. The most frequent adverse events in both groups were hypoglycemia, headache, and nasopharyngitis. CONCLUSIONS: IDegAsp + IAsp was non-inferior to IDet + IAsp regarding HbA1c, had similar hypoglycemia rates and required fewer injections.

Association Between the Use of Long-Acting Insulin and Hypoglycemia in Nondiabetic Patients in the Surgical Intensive Care Unit.

PURPOSE: The purpose of this study was to examine the association between long-acting insulin and hypoglycemia in nondiabetic surgical intensive care patients. METHODS: This single-center, retrospective cohort study evaluated glycemic control in nondiabetic critically ill surgical patients receiving long-acting insulin plus sliding scale versus those receiving sliding scale alone. Patients were matched based on sliding scale order and type of surgery. The primary outcome was the proportion of patients who experienced hypoglycemia (glucose values <70 mg/dL). Secondary outcomes included comparing the distribution of glycemic events in the 2 groups and describing the proportion of patients transferred out of the intensive care unit on long-acting insulin who experienced hypoglycemia. RESULTS: One hundred twenty patients met the study criteria. Hypoglycemia was significantly higher in the long-acting insulin plus sliding scale group compared to those receiving sliding scale alone (17 [28.3%] patients vs 8 [13.3%] patients; P = .047). After adjusting for body mass index, renal failure, age, and Acute Physiology and Chronic Health Evaluation II, the odds of hypoglycemia were 4.1 times higher for patients receiving long-acting insulin and sliding scale compared to those receiving sliding scale alone ( P = .02). There were more hypoglycemic events (42 vs 20; P = .05) and hyperglycemic events (313 vs 135; P = .02) in the long-acting insulin group. CONCLUSION: This study demonstrated higher rates of hypoglycemia associated with the utilization of long-acting insulin in nondiabetic surgical intensive care patients. Risk of hypoglycemia should be weighed against possible benefits in this population.

Long-acting insulin analogs and cancer.

AIMS: Hyperinsulinemia is a recognized risk factor for cancer and plays a major role for the increased cancer incidence in diabetic patients. Whether insulin analogs, and particularly long-acting analogs, worsen the pro-cancer effect of excess insulin is still controversial. DATA SYNTHESIS: In this paper we summarize the biological bases for the potential detrimental effect of long-acting analogs on cancer cells and review the in vitro and in vivo evidence on this issue. Because of their different molecular structure relative to native insulin, insulin analogs may activate the insulin receptor (IR) and the post receptor pathways differently. Most, but not all, in vitro evidence indicate that long-acting analogs may have a stronger mitogenic potency than insulin on cancer cells. Notably insulin glargine, the most studied long-acting analog, also has a higher affinity for the insulin-like growth factor (IGF)-1 receptor, a potent growth mediator. In vitro observations, however, may not reflect what occurs in vivo when analogs are metabolized to derivatives with a different mitogenic activity. Clinical studies, mostly retrospective and predominantly concerning glargine, provide contrasting results. The only perspective trial found no cancer increase in patients treated with glargine. All these studies, however, have severe weaknesses because of the insufficient evaluation of important factors such as dose administered, length of exposure, patient follow-up duration and site-specific cancer investigation. Moreover, whether cancer promotion is a long-acting analog class characteristic or a specific effect of a single agent is not clear. CONCLUSIONS: In conclusion the carcinogenic risk of long-acting analogs, and specifically glargine, can be neither confirmed nor excluded. A personalized and shared decision, considering all the individual risk factors (metabolic and non-metabolic), is the suggestion for the clinician.

A 26-week, randomized trial of insulin detemir versus NPH insulin in children and adolescents with type 2 diabetes (iDEAt2).

There are limited studies evaluating the safety and efficacy of treatments in young people with type 2 diabetes (T2D). This study compared the efficacy and safety of insulin detemir versus neutral protamine Hagedorn (NPH) insulin, both in combination with metformin and lifestyle intervention, in children and adolescents with T2D. This randomized, open-label, phase 3 trial recruited patients (n = 42) aged 10-17 years diagnosed with T2D already receiving metformin ± other oral antidiabetic drugs ± basal insulin. Patients were randomized (1:1) to receive either insulin detemir or NPH insulin, both with the maximum tolerated dose of metformin, and lifestyle intervention, over 26 weeks. Enrollment terminated prematurely after 17 months due to a very slow recruitment rate (12% of the target met). After 26 weeks, the observed mean HbA1c value had decreased by 0.61% points in the insulin detemir group vs. 0.84% points in the NPH insulin group. The rate of symptomatic blood glucose-confirmed hypoglycemic episodes was 0.4 episodes/patient-year of exposure (PYE) for insulin detemir vs. 1.1 episodes/PYE for NPH insulin. CONCLUSION: No safety issues were revealed with either basal insulin. Due to the low number of patients recruited, no efficacy conclusions could be drawn. ClinicalTrials.gov identifier: NCT02131272. What is known: • There is a growing worldwide epidemic of type 2 diabetes in children and adolescents. • There is a lack of research and limited treatment options currently available in this population. What is new: • No safety issues with insulin detemir or neutral protamine Hagedorn insulin in children and adolescents with type 2 diabetes were observed. • Improving clinical trial recruitment, along with providing early, efficacious, and safe treatment options, in this population is critical.

Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study.

AIMS/HYPOTHESIS: The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. METHODS: National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2010) and Sweden (2007-2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (≤0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6 and >6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. RESULTS: A total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for ≤0.5 years of treatment and for malignant melanoma for 2-3 years (RR 1.92, 95% CI 1.02, 3.61) and 4-5 years (RR 3.55, 95% CI 1.68, 7.47]); among men, a lower risk was observed for pancreatic cancer for 2-3 years (RR 0.34, 95% CI 0.17, 0.66) and for liver cancer for 3-4 years (RR 0.36, 95% CI 0.14, 0.94) and >6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences. CONCLUSIONS/INTERPRETATION: The present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years.

Design and rationale of a large, international, prospective cohort study to evaluate the occurrence of malformations and perinatal/neonatal death using insulin detemir in pregnant women with diabetes in comparison with other long-acting insulins.

BACKGROUND: There are a lack of data regarding the effect of basal insulin analogues on rates of events like congenital malformation and perinatal mortality in diabetic pregnancy. METHODS: The present study is a prospective, non-interventional, multicentre cohort study conducted in seven countries, designed to assess the safety of insulin detemir during pregnancy, and to monitor the health status of resulting infants (exposed in utero) up to 1 year of age. The study population includes women with type 1 or type 2 diabetes, who are pregnant and being treated with insulin. Data will be collected in the context of routine practice. The primary endpoint is the proportion of pregnancies in women treated with insulin detemir, compared with other basal insulin regimens, which do not result in any of the following events: major congenital malformations, perinatal death or neonatal death. A sample size of 3075 pregnancies was calculated to provide an 80% power to detect a difference of 3.5% between groups in the primary endpoint at a 5% level. DISCUSSION: The study will also examine other important maternal endpoints (e.g., incidences of severe hypoglycaemia and pre-eclampsia) and perinatal outcomes such as overweight neonates, as well as infant outcomes at 1 year of age. It has a fixed recruitment period from 2013 to 2018, enrolling all eligible patients, and is expected to inform future prescribing with basal insulins in diabetic pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01892319 (date registered: 27.06.2013).

Insulin Detemir in Combination with Oral Antidiabetic Drugs Improves Glycemic Control in Persons with Type 2 Diabetes in Near East Countries: Results from the Lebanese Subgroup.

OBJECTIVE: To evaluate the effectiveness and safety of insulin detemir treatment as add-on therapy in a real-world setting of Lebanese insulin naïve persons, with type 2 diabetes poorly controlled on oral antidiabetic drugs (OADs). METHODS: Our study was a prospective, observational study representing the Lebanese arm of the multinational prospective and observational study involving 2,155 persons across Near East countries, Lebanon, Pakistan, Israel and Jordan. Effectiveness endpoints were changes in HbA1c, fasting and post-prandial glucose (FPG, PPG) after 24 weeks of treatment with insulin detemir in eligible persons. Safety endpoints were number of hypoglycemic events, incidence of adverse drug reactions (ADRs), serious ADRs, adverse events, and body weight change between baseline and end of treatment. RESULTS: 868 persons were included (mean age: 59.5 ± 10.4 years, men: 55.3%). Glycemic control improved with significant reduction in mean HbA1c from 9.7 ± 1.6% to 7.2 ± 1% (P<.0001). The percentage of persons who achieved the target of HbA1c<7% increased from .7% at baseline to 39% at week 24. Mean FPG decreased significantly from 213.7 ± 60.1 mg/dL to 120.3 ± 25.7 mg/dL (P<.001), and mean PPG from 271 ± 65.3 mg/dL to 158.1 ± 36.4 mg/dL (P<.0001). The rate of major hypoglycemic episodes decreased from .1498 at baseline to .0448 at week 24. Three adverse events but no ADR or serious ADR were reported. Body weight decreased from 80.4±13.2 Kg to 79.9±12.5 Kg (P<.0001). CONCLUSIONS: Initiating insulin detemir in a clinical health care setting among Lebanese with type 2 diabetes mellitus on OADs improves glycemic control with no increase in hypoglycemia, adverse events or weight compared with baseline.

Adiponectin, Leptin, and Leptin Receptor in Obese Patients with Type 2 Diabetes Treated with Insulin Detemir.

The aim of the present study is to quantitatively assess the expression of selected regulatory molecules, such as leptin, leptin receptor, and adiponectin in the blood of obese patients with type 2 diabetes both before treatment and after six months of pharmacological therapy with the long-lasting insulin analogue, insulin detemir. A significant decrease in the analysed regulatory molecules, i.e., leptin receptor and adiponectin, was found in blood plasma of the patients with untreated type 2 diabetes. These changes were accompanied by an increase in plasma leptin concentrations. Insulin treatment resulted in the normalization of plasma leptin receptor and adiponectin concentrations. The circulating leptin level did not change following anti-diabetic therapy with insulin detemir. Gender was a significant factor modifying the circulating level of all the analysed regulatory active compounds. Bioinformatic analysis was performed using Matlab with the Signal Processing Toolbox. The conducted discriminant analysis revealed that the leptin receptor, Δw(19), and adiponectin, Δw(21), were the parameters undergoing the most significant quantitative changes during the six-month therapy with insulin detemir. The conducted examinations indicated the contribution of adipocytokines-the biologically-active mediators of systemic metabolism, such as leptin and adiponectin in the pathomechanism of disorders being the basis for obesity which leads to development of insulin resistance, which, in turn, results in the occurrence of type 2 diabetes.

Risk stratification of persons on premixed insulin in Ramadan.

The International Diabetes Federation (IDF), in collaboration with the Diabetes and Ramadan (DAR) International Alliance, has recently published practical guidelines on the management of diabetes and Ramadan .The risk stratification categorizes all persons wishing to fast into three groups, based upon potential risk. In spite of evidence to the contrary, all persons using premixed insulin are categorized as having high risk. In this article, we present data from randomized controlled trials, and discuss the placement of premixed insulin in the risk stratification framework.

The past, present, and future of basal insulins.

Insulin production by the pancreas follows a basic pattern where basal levels of insulin are secreted during fasting periods, with prandial increases in insulin associated with food ingestion. The aim of insulin therapy in patients with diabetes is to match the endogenous pattern of insulin secretion as closely as possible without causing hypoglycaemia. There are several optimal pharmacokinetic and pharmacodynamic properties of long-acting basal insulins that can help to achieve this aim, namely, as follows: activity that is flat and as free of peaks as possible, a duration of action of ≥24-h, and as little day-to-day variation as possible. The long-acting basal insulins are a fundamental therapy for patients with type 1 and type 2 diabetes, and those that are currently available have many benefits; however, the development of even longer-acting insulins and improved insulin delivery techniques may lead to better glycemic control for patients in the future. Established long-acting basal insulins available in the United States and Europe include insulin glargine 100 units/mL and insulin detemir, both of which exhibit similar glycemic control to that of the intermediate-acting neutral protamine Hagedorn insulin, but with a reduction in hypoglycaemia. Newer insulin products available include new insulin glargine 300 units/mL (United States and Europe) and the ultra-long-acting insulin degludec (Europe) with basal insulin peglispro currently in development. These new insulins demonstrate different pharmacokinetic/pharmacodynamic profiles and longer durations of action (>24 h) compared with insulin glargine 100 units/mL, which may lead to potential benefits. The introduction of biosimilar insulins may also broaden access to insulins by reducing treatment costs. Copyright © 2015 John Wiley & Sons, Ltd.

Comparison of insulin degludec with insulin detemir in type 1 diabetes: a 1-year treat-to-target trial.

The long-term safety and tolerability of insulin degludec (IDeg) was compared with that of insulin detemir (IDet), as basal treatment in participants with type 1 diabetes mellitus (T1DM). In the present multinational, 26-week core + 26-week extension, controlled, open-label, parallel-group trial, adults with T1DM were randomized to IDeg or IDet as basal insulin treatment combined with meal-time bolus insulin aspart. IDeg was administered once daily, whilst IDet was administered once or twice daily depending on patients' glycaemic control. After 1 year, IDeg provided a 33% lower rate of nocturnal hypoglycaemia compared with IDet: estimated rate ratio (IDeg : IDet) 0.67 [95% confidence interval (CI) 0.51; 0.88]; p < 0.05. IDeg improved glycated haemoglobin after 1 year of treatment, similarly to IDet, but IDeg also provided a significantly greater reduction in fasting plasma glucose compared with IDet: estimated difference (IDeg - IDet) -1.11 (95% CI -1.83; -0.40) mmol/l; p < 0.05. The present study confirmed the long-term safety and tolerability profile of IDeg in patients with T1DM. IDeg provided a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Long-acting insulin analog detemir displays reduced effects on adipocyte differentiation of human subcutaneous and visceral adipose stem cells.

BACKGROUND AND AIMS: Since treatment with insulin detemir results in a lower weight gain compared to human insulin, we investigated whether detemir is associated with lower ability to promote adipogenesis and/or lipogenesis in human adipose stem cells (ASC). METHODS AND RESULTS: Human ASC isolated from both the subcutaneous and visceral adipose tissues were differentiated for 30 days in the presence of human insulin or insulin detemir. Nile Red and Oil-Red-O staining were used to quantify the rate of ASC conversion to adipocytes and lipid accumulation, respectively. mRNA expression levels of early genes, including Fos and Cebpb, as well as of lipogenic and adipogenic genes, were measured at various phases of differentiation by qRT-PCR. Activation of insulin signaling was assessed by immunoblotting. ASC isolated from subcutaneous and visceral adipose tissue were less differentiated when exposed to insulin detemir compared to human insulin, showing lower rates of adipocyte conversion, reduced triglyceride accumulation, and impaired expression of late-phase adipocyte marker genes, such as Pparg2, Slc2a4, Adipoq, and Cidec. However, no differences in activation of insulin receptor, Akt and Erk and induction of the early genes Fos and Cebpb were observed between insulin detemir and human insulin. CONCLUSION: Insulin detemir displays reduced induction of the Pparg2 adipocyte master gene and diminished effects on adipocyte differentiation and lipogenesis in human subcutaneous and visceral ASC, in spite of normal activation of proximal insulin signaling reactions. These characteristics of insulin detemir may be of potential relevance to its weight-sparing effects observed in the clinical setting.

Insulin detemir versus glyburide in women with gestational diabetes mellitus.

AIM: To evaluate the safety, efficacy and pregnancy outcomes of insulin detemir (IDet) versus glyburide treatment in women with gestational diabetes mellitus (GDM). METHODS: We conducted a retrospective cohort study of women with GDM who were treated with either glyburide or IDet for GDM in a university-affiliated tertiary hospital. RESULTS: Ninety-one patients with GDM were enrolled, 62 were administered glyburide and 29 IDet. Maternal age, pregestational body mass index (BMI) and rate of abnormal oral glucose tolerance test (OGTT) blood glucose values were not significantly different between groups. Good glycemic control rates were comparable. Hypoglycemic episodes were reported only in the glyburide group (19.4% versus 0%, p = 0.01). Maternal weight gain during pregnancy was significantly higher among women in the glyburide group (8.8 ± 5.1 kg, p < 0.001) compared to those in the IDet group (2.1 ± 19.9 kg, p = 0.71). CONCLUSIONS: To the best of our knowledge, this is the first study on IDet treatment in patients with GDM. By our preliminary results, IDet is a viable treatment option in women with GDM. Further large prospective studies are needed to determine the efficacy and safety of IDet in GDM patients.

A patient centred approach to basal insulin choice for the management of type 2 diabetes mellitus.

Basal insulins are first line injectable therapy by all international guidelines. Basal insulins can be used alone, in combination with metformin, dual or triple oral therapy, glucagon-like peptide receptor agonists, or prandial insulin. However, all basal insulins are not similar. This article proposes objective parameters, and suggests a simple checklist, using history, physical examination, and investigations, to help choose the appropriate preparation, viz degludec, detemir, glargine or NPH insulin, for persons requiring basal insulin.

Choosing injectable therapy: The metabolic fulcrum.

This clinical decision making hypothesis utilizes the metabolic fulcrum based approach to classify persons with diabetes into three categories: predominantly catabolic, eubolic, and predominantly [maladaptive] anabolic. This systematic arrangement helps define choice of injectable therapy in type 2 diabetes mellitus. Patients with predominant catabolism, may respond better to intensive insulin therapy. Dual action insulin, including premixed insulin and I Deg Asp (insulin degludec aspart), may be an acceptable alternative. Uncomplicated, eumetabolic patients with type 2 diabetes may use any of the various drugs available. Patients classified as having maladaptive anabolism may benefit from a GLP1RA. If this does not suffice, a GLP1RA + basal insulin combination may be effective.

Insulin therapy in pregnancy.

Insulin is the mainstay of pharmacotherapy in pregnancy complicated by diabetes. This review covers the various insulin regimes and preparations, explaining how to use them, and decide appropriate doses in pregnancy. It approaches insulin treatment from a patient - centred, as well as physician and obstetrician friendly viewpoint, providing pragmatic guidance for management of diabetes in pregnancy.