insulin-detemir and Obesity

Despite their widespread use in this population, data on the pharmacodynamic (PD) properties of the insulin analogs detemir and glargine in severely obese patients with type 2 diabetes are lacking.. The primary objective of the study was to compare the PD properties of two different doses of the basal insulin analogs detemir and glargine in patients with type 2 diabetes and a BMI > 35 kg/m2. PD data were derived from euglycemic clamp studies over 30 hours and each subject was studied for four times after the subcutaneous injection of a lower (0.8 U/kg body weight) and higher (1.6 U/kg body weight) dose of both detemir and glargine using a single-blind, randomised cross-over design.. Six male and four female patients with type 2 diabetes and a mean BMI of 43.2±5.1 kg/m2 (mean age 55.7±2 years, mean HbA1c 7.2±0.3%) completed the study. The total GIRAUC0-30 (mean difference 1224 mg/kg, 95%CI 810-1637, p = 0.00001), GIRAUC0-24 (mean difference 1040 mg/kg, 95%CI 657-1423; p = 0.00001), GIRAUC24-30 (mean difference 181 mg/kg, 95%CI 64-298; p = 0.004), GIRmax (mean difference 0.93 mg/kg/min, 95%CI 0.22-1.64, p = 0.01) and time to GIRmax (+1.9 hours, 95%CI 0.5-3.2; p = 0.009) were higher after the higher doses of both insulins, without significant differences between detemir and glargine. However, during the last 6 hours of the clamp the GIRAUC24-30 was significantly increased with glargine (mean difference 122 mg/kg, 95%CI 6-237, p = 0.043), reflecting a more pronounced late glucose lowering effect.. A clear dose-response relationship can be demonstrated for both insulin analogs, even at very high doses in severely obese patients with type 2 diabetes. Compared to detemir, glargine has a more pronounced late glucose lowering effect 24-30 h after its injection.. Controlled-Trials.com ISRCTN57547229.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucose Clamp Technique; Humans; Insulin Detemir; Insulin Glargine; Male; Middle Aged; Obesity

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.

Topics: Adiponectin; Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Insulin Detemir; Leptin; Male; Middle Aged; Obesity; Receptors, Leptin; Sex Factors

To compare the effects of the basal insulin analogues glargine and detemir on endothelial function and adipocytokine levels in people with Type 2 diabetes.. We studied 32 people with Type 2 diabetes whose blood glucose control was unsatisfactory while receiving only oral hypoglycaemic drugs. Participants were randomized to either insulin glargine or detemir for 24 weeks and then crossed over to the other treatment without a washout period. Flow-mediated vasodilatation, adipocytokine levels (plasminogen activator inhibitor-1 and leptin/adiponectin ratio), and fasting ghrelin levels were monitored.. These results suggest that the effect on endothelial function and adipocytokine profiles may differ between glargine and detemir in people with diabetes (Trial registration ID: UMIN000004973).

Topics: Adipokines; Adiponectin; Adult; Aged; Ankle Brachial Index; C-Reactive Protein; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Ghrelin; Humans; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Leptin; Male; Middle Aged; Obesity; Plasminogen Activator Inhibitor 1; Vasodilation; Young Adult

Weight gain upon insulin initiation is opposite to clinical goals in diabetes management. This trial aimed to determine the impact of modest dietary intervention on weight change and examine weight change in baseline body mass index strata when initiating once-daily insulin detemir (IDet) in overweight or obese insulin-naïve individuals with type 2 diabetes (T2D).. DIET (Impact of Dietary Intervention on Weight Change in Subjects With Type 2 Diabetes) was a 26-week, randomized, treat-to-target, stratified, controlled, open-label, multinational trial. Subjects were randomized 1 : 1 to either the IDet group, which received basic dietary and physical exercise advice at baseline, or the Diet+IDet group, which had additional dietary consultations with a certified dietician (three face-to-face meetings, three phone contacts).. Mean estimated change in body weight from baseline ± standard error (SE) was -1.05 ± 0.23 kg for Diet+IDet and -0.56 ± 0.23 kg for IDet alone. Estimated mean difference was 0.49 kg (95% confidence interval: -0.15; 1.13, p = 0.132). Glycaemic control, measured by haemoglobin A1c (HbA1c) and fasting plasma glucose, improved similarly in both groups. Both groups reported variable reductions in caloric intake and overall physical activity levels. No difference in hypoglycaemia rates between groups was observed.. This study suggests that a modest dietary intervention plus basic lifestyle advice, compared with basic lifestyle advice alone, resulted in similar weight change, efficacy, safety and tolerability when initiating IDet once daily in overweight or obese insulin-naïve individuals with T2D.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Directive Counseling; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Detemir; Insulin, Long-Acting; Male; Obesity; Risk Reduction Behavior; Treatment Outcome; Weight Loss

The aim of study was to evaluate the safety and efficacy of insulin detemir as a basal insulin switching from neutral protamine Hagedorn insulin (NPH) and insulin glargine in patients with diabetes on an intensive insulin therapy regimen.. This 6-month multicentre, prospective, treat-to-target [glycosylated haemoglobin (HbA(1c) ) less than 6.5%] trial included 92 people with diabetes (61 type 1, 29 type 2 and two unknown diabetes types). Detemir was administered first with fixed dose and injection times and then adapted to optimal dose after 3 months.. Mean HbA(1c) (%) of all the subjects at months 4 to 6 of the study was improved compared with month 0 (7.34 ± 0.87, 7.28 ± 0.88, 7.25 ± 0.93 vs. 7.55 ± 1.18; p < 0.05 paired t-test). However, significant improvement was seen only among the patients who had previously used NPH as a basal insulin. Twice-daily injection of basal insulin increased among people in the type 1 previously injected insulin glargine. Total insulin dose increased in the type 1 glargine group. The mean body weight change in the highest quartile body mass index (BMI) group was from 70.7 to 69.3 kg over the 6 months. Quality of life (QoL) relating to the patients' glycaemic control tended to improve without a change in frequency of hypoglycaemia.. The results suggest that insulin detemir has a greater effect on glycaemic control in subjects with poor glycaemic control using NPH; can reduce or maintain body weight in obese patients; and obtains perceptive stability for patients with unstable glycaemic control.

Topics: Adult; Aged; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Middle Aged; Obesity; Prospective Studies; Treatment Outcome; Weight Loss

Several studies suggest benefits of insulin analogues detemir or glulisine in overweight and obese patients with type 2 diabetes. The present multicentre study therefore examines, whether these insulin analogues are used more frequently in patients with increased body mass index.. Data of 38 560 adult type 2 diabetic patients using insulin analogues, from 150 centres in Germany, registered in a standardized, prospective, computer-based documentation program (DPV), were included. Patients were classified into body mass index categories according to World Health Organization. Analysis was stratified by 3 time periods. To adjust for confounding effects, multivariable logistic regression models were created.. Detemir was preferentially used in overweight (OR 1.36, 95%-CI 1.20-1.53) and obese patients (OR 2.06, 95%-CI 1.84-2.31) compared to normal-weight patients. These effects remained significant after adjusting for sex, age, new/old federal state of Germany, size of centre, treatment in university clinic and clinic/specialized private practice. Models were additionally adjusted for time period and interaction of BMI category with age or sex. For glulisine, a minor effect was present when comparing obese to normal-weight patients (OR 1.26, 95%-CI 1.06-1.50). After adjustment, this finding was no longer significant. Stratified by obesity grade, class III obese patients more frequently used detemir or glulisine compared to class I obese patients. Comparing time periods, odds ratios did not differ, neither for detemir nor for glulisine..  Detemir is used more often in overweight and obese patients compared to normal-weight patients. For glulisine, the relationship is less pronounced.

Topics: Aged; Body Weight; Databases, Factual; Diabetes Mellitus, Type 2; Drug Prescriptions; Female; Germany; Humans; Hypoglycemic Agents; Insulin; Insulin Detemir; Insulin, Long-Acting; Male; Middle Aged; Obesity; Overweight; Practice Patterns, Physicians'; Registries

Insulin therapy using insulin detemir (d-INS) has demonstrated weight-sparing effects compared with other insulin formulations. Mechanisms underlying these effects, however, remain largely unknown. Here we postulate that the intestinal tissues' selective preference allows d-INS to exert enhanced action on proglucagon (Gcg) expression and the production of glucagon-like peptide (GLP)-1, an incretin hormone possessing both glycemia-lowering and weight loss effects. To test this hypothesis, we used obese type 2 diabetic db/db mice and conducted a 14-day intervention with daily injection of a therapeutic dose of d-INS or human insulin (h-INS) in these mice. The body weight of the mice after 14-day daily injection of d-INS (5 IU/kg) was decreased significantly compared with those injected with the same dose of h-INS or saline. The weight-sparing effect of d-INS was associated with significantly elevated circulating levels of total GLP-1 and reduced food intake. Histochemistry analysis demonstrated that d-INS induced rapid phosphorylation of protein kinase B (Akt) in the gut L cells of normal mice. Western blotting showed that d-INS stimulated Akt activation in a more rapid and enhanced fashion in the mouse distal ileum compared with those by h-INS. In vitro investigation in primary fetal rat intestinal cell (FRIC) cultures showed that d-INS increased Gcg mRNA expression as determined by Northern blotting and real-time RT-PCR. Consistent with these in vivo investigations, d-INS significantly increased GLP-1 secretion in FRIC cultures. Consistently, d-INS was also shown to induce rapid phosphorylation of Akt in the clonal gut cell line GLUTag. Furthermore, d-INS increased β-catenin phosphorylation, its nuclear translocation, and enhanced cAMP response element-binding protein (CREB) phosphorylation in a phosphatidylinositol 3-kinase and/or mitogen-activated protein kinase kinase/extracellular signal-regulated kinase-sensitive manner. We suggest that the weight-sparing benefit of d-INS in mice is related to its intestinal tissues preference that leads to profound stimulation of Gcg expression and enhanced GLP-1 secretion in intestinal L cells, potentially involving the activation of insulin/β-catenin/CREB signaling pathways.

Topics: Animals; beta Catenin; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus, Type 2; Fetus; Gene Expression Regulation; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Detemir; Insulin, Long-Acting; Intestinal Mucosa; L Cells; Mice; Mice, Mutant Strains; Obesity; Organ Specificity; Phosphorylation; Proglucagon; Protein Processing, Post-Translational; Rats; Rats, Wistar; RNA, Messenger

Insulin has anti-inflammatory effects in short-term experiments. However, the effects of chronic insulin administration on inflammation are unknown. We hypothesised that chronic insulin administration would beneficially alter adipose tissue inflammation and several circulating inflammatory markers.. We administered two forms of long-acting insulin, insulin glargine (A21Gly,B31Arg,B32Arg human insulin) and insulin detemir (B29Lys[ε-tetradecanoyl],desB30 human insulin), to LDL-receptor-deficient mice. After 8 weeks on a diet that causes obesity, hyperglycaemia, adipose tissue macrophage accumulation and atherosclerosis, the mice received subcutaneous glargine, detemir or NaCl (control) for 12 weeks. Serum amyloid A (SAA) and serum amyloid P (SAP), metabolic variables, adipose tissue macrophages and aortic atherosclerosis were evaluated.. Weight gain was equivalent in all groups. The glycated haemoglobin level fell equivalently in both insulin-treated groups. Plasma cholesterol and triacylglycerol levels, and hepatic triacylglycerol level significantly improved in the glargine compared with the detemir or control groups. Levels of mRNA expression for monocyte chemotactic protein-1 and F4/80, a macrophage marker, in adipose tissue were decreased only in the glargine group (p < 0.05). Visceral adipose tissue macrophage content decreased in both insulin groups (p < 0.05), whereas atherosclerosis decreased only in the glargine group. Circulating SAA and SAP did not decrease in either insulin-treated group, but IL-6 levels fell in the glargine-treated mice.. While chronic insulin administration did not decrease SAA and SAP, administration of glargine but not detemir insulin improved dyslipidaemia, IL-6 levels and atherosclerosis, and both insulins reduced macrophage accumulation in visceral adipose tissue. Thus, chronic insulin therapy has beneficial tissue effects independent of circulating inflammatory markers in this murine model of diet-induced obesity and diabetes.

Topics: Adipose Tissue; Animals; Atherosclerosis; Body Composition; Immunohistochemistry; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Macrophages; Male; Mice; Mice, Knockout; Obesity; Polymerase Chain Reaction; Receptors, LDL; Weight Gain

Topics: Amino Acid Substitution; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Obesity

Topics: Adiposity; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Diet Therapy; Humans; Insulin; Insulin Detemir; Insulin, Long-Acting; Leptin; Obesity; Piperidines; Pyrazoles; Rimonabant