Metabolism of Insulin Glargine After Repeated Daily Subcutaneous Injections in Subjects With Type 2 Diabetes

OBJECTIVE

To investigate concentration of plasma insulin glargine after its subcutaneous dosing compared with concentration of its metabolites 1 (M1) and 2 (M2) in subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Nine subjects underwent a 32-h euglycemic glucose clamp study (0.4 units/kg glargine after 1 week of daily glargine administration). Glargine, M1, and M2 were measured by a specific liquid chromatography-tandem mass spectrometry assay.

RESULTS

Glargine was detected in only five of the nine subjects, at few time points, and at negligible concentrations. M1 was detected in all subjects and exhibited the same pattern as traditional radioimmunoassay-measured plasma insulin. M2 was not detected at all.

CONCLUSIONS

After subcutaneous injection, glargine was minimally detectable in blood, whereas its metabolite M1 accounted for most (>90%) of the plasma insulin concentration and metabolic action of the injected glargine.After subcutaneous injection in vivo, the long-acting insulin analog glargine undergoes a sequential cleavage of the COOH terminus of the B-chain–forming metabolites M1 and M2 (1,2). M1 and M2 fully retain the same metabolic properties as human insulin (HI), but in contrast to glargine, they do not differ from HI in affinity for IGF-1 receptor (IGF-1R) and mitogenesis (3). In the companion article in this issue (Bolli et al. [4]), glargine metabolism has been studied in subjects with type 1 diabetes, but there are no data on type 2 diabetes. The aim of the current study was to shed light on this question.     

Factors Associated With Psychological Insulin Resistance in Individuals With Type 2 Diabetes

OBJECTIVE

To describe the predictive relationships of selected sociodemographic, biomedical, and psychosocial variables to reluctance to use insulin among patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 178 patients with type 2 diabetes participated in this cross-sectional, observational study. Data were obtained by patient interview using validated measures of diabetes attitude, knowledge, self-efficacy, care communication, and perceived barriers to treatment, as well as sociodemographic and biomedical data.

RESULTS

Women and ethnic minorities with type 2 diabetes have more psychological barriers to insulin treatment (P < 0.05). The final regression model showed that individuals who believed in the value of tight glucose control, had strong self-efficacy, and had better interpersonal processes with their healthcare providers were less reluctant to use insulin treatment (R² = 0.403; P < 0.0001).

CONCLUSIONS

Diabetes self-efficacy and better interaction with clinicians were important in decreasing patients'' reluctance to use insulin, known as psychological insulin resistance.Despite the known benefits of insulin, many patients are reluctant to use insulin therapy (1–3). A patient''s reluctance to initiate insulin may be called “psychological insulin resistance” (PIR).Little is known about what factors influence PIR. We examined the relationships among PIR, sociodemographic, biomedical, and psychosocial factors identified in previous studies (4–7) and tested a predictive model of PIR.     

Oral Insulin: A Comparison With Subcutaneous Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

To determine the pharmacokinetic and pharmacodynamic properties of an oral insulin (OI) formulation compared with subcutaneously injected regular human insulin (RHI).

RESEARCH DESIGN AND METHODS

Ten male patients with type 2 diabetes (means ± SD; A1C 7.0 ± 1.1%; BMI 28.3 ± 2.7 kg/m²) received either 300 units of insulin combined with 400 mg of delivery agent orally or 15 units RHI subcutaneously under isoglycemic clamp conditions.

RESULTS

Maximum insulin concentration was greater and onset of action was faster with OI (C_max 93 ± 71 vs. 33 ± 11 μU/ml; AUC_GIR^(0−1h) 173 ± 86 vs. 27 ± 32 mg/kg; P < 0.05). Mean insulin concentration and glucose infusion rate returned to baseline within 3 h after OI administration. Relative bioavailability of OI was 7 ± 4% (1st 2 h).

CONCLUSIONS

This proof-of-concept study demonstrated that absorption of OI is feasible under fasting conditions. OI has a fast onset and a short duration of action but also shows a rather high between-subject variability in absorption.Oral administration of insulin has the potential advantage of a more physiological action by its direct effect on hepatic glucose production (1,2). Thus far various oral insulin approaches however have only partially produced satisfactory results (1,3,4). Gastrointestinal absorption of insulin is hampered by factors such as enzymatic degradation and lack of permeation through epithelial cells (5). Noncovalent interaction of the novel drug-carrier molecule monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (4-CNAB) with insulin might create more favorable physico-chemical properties for gastrointestinal insulin absorption (6,7). In this study, 4-CNAB has been combined with human insulin to facilitate gastrointestinal insulin absorption.     

Cost-effectiveness of Insulin Degludec Versus Insulin Glargine in Insulin-naive Chinese Patients With Type 2 Diabetes

Purpose

The goal of this study was to investigate the long-term economic outcomes of insulin degludec versus insulin glargine use in Chinese patients with type 2 diabetes mellitus (T2DM) whose oral antidiabetic drugs did not provide sufficient glycemic control.

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured.

RESULTS

Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity.

CONCLUSIONS

Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.Type 2 diabetes is closely related to atherosclerosis and the development of cardiovascular complications such as myocardial infarction or stroke. Recent studies on cardiovascular end points in patients with type 2 diabetes call into question the value of A1C-focused treatments in reducing macrovascular complications of diabetes (1–3). Other markers such as glucose excursions, hypoglycemia, or postprandial generation of oxidative stress may add important information for the judgment of cardiovascular risk in patients with type 2 diabetes (1,2). Postprandial microvascular blood flow is under dynamic regulation and is diversely affected by changes in postprandial glucose and insulin levels (4). Increasing postprandial insulin levels stimulate microvascular blood flow by inducing the endothelial release of nitric oxide via the activation of the phosphatidylinositol 3-kinase system (5,6). In contrast, increasing blood glucose levels were shown to oppose the insulin effects on endothelial cells and to impair postprandial microvascular blood flow (7). A reduced first-phase insulin release with an augmented increase in postprandial glucose levels followed by an impairment in endothelial function and postprandial microvascular blood flow is an early feature of type 2 diabetes (4,8). These findings suggest that a physiological timing of prandial insulin release fulfills an important role not only in controlling postprandial blood glucose levels but also in maintaining normal tissue perfusion and nutrition. In addition, recent studies have shown that in insulin-treated patients with type 1 and type 2 diabetes, the pharmacokinetic profile of insulin formulations affects postprandial microvascular blood flow and that treatment with fast-acting insulin analogs reduces postprandial oxidative stress and restores endothelial function more effectively than treatment with human regular insulin (9–11).VIAject is a new, ultra–fast-acting insulin formulation shown to have more rapid insulin absorption than that for human regular insulin and insulin lispro. The aim of this study was to compare the effect of preprandial subcutaneous administration of insulin VIAject with preprandial application of human regular insulin and insulin lispro on several markers of endothelial and microvascular function after a standardized liquid meal test in patients with type 2 diabetes.     

Insulin Therapy in People With Type 2 Diabetes: Opportunities and Challenges?

Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes.     

Prandial Insulin Dosing Using the Carbohydrate Counting Technique in Hospitalized Patients With Type 2 Diabetes

OBJECTIVE

To compare a modified fixed meal dosing strategy to flexible meal dosing in hospitalized patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Patients (N = 126) with refractory hyperglycemia or requiring at least 20 units of insulin per day were randomly assigned to fixed meal dosing (including withholding the dose if less than half of the meal tray was consumed) or flexible meal dosing based upon carbohydrate intake. The inpatient diabetes management team made all treatment adjustments. Outcomes included day 3 mean glucose, 72-h glucose trend analysis, hypoglycemia (<3.9 mmol/L), and inpatient diabetes treatment satisfaction.

RESULTS

The mean glucose on day 3 was 9.5 and 8.8 mmol/L in the fixed and flexible meal groups, respectively (P = 0.26). The frequency of hypoglycemia was 23 and 39% overall in the fixed and flexible meal groups (P = 0.08), with half of events occurring in the morning. There was a wide range of carbohydrate intake (median 51 g/meal, 10–90% range 26–72 g on day 3). The fixed dose group required significantly more prandial insulin overall and more correction insulin over time. There was no difference in composite treatment satisfaction or dosing miscalculations between groups.

CONCLUSIONS

A fixed meal dosing strategy provided similar glucose control as flexible meal dosing, when managed by an inpatient diabetes treatment team. However, a larger sample size would be needed to definitively evaluate a treatment effect of flexible meal dosing in the hospital. Further study is needed to improve the delivery of bolus insulin in hospitalized patients.Hyperglycemia is common in the hospital (1) and is associated with poor outcomes (2). Subcutaneous insulin is traditionally favored for most general surgical and medical patients outside of the intensive care unit, using a regimen that includes basal, prandial, and correction insulin components (3,4). However, there are limited data to support individualized treatment approaches, particularly outside of the intensive care unit, where most patients receive care. In general, glycemic control is related to the intake of carbohydrates (5) and is limited by the occurrence of hypoglycemia. Data suggest that the most common cause of hypoglycemia in hospitalized patients with diabetes is a reduction in caloric intake (6,7). Variable carbohydrate exposure may be a result of tests that require fasting, late meal trays, patient food preferences, or symptoms that interfere with nutritional intake, such as anorexia and nausea. Therefore, optimizing prandial insulin dosing may provide better glycemic control.One approach to optimize prandial insulin coverage is to deliver meals with fixed carbohydrate content, thereby enabling fixed meal dosing (4). However, this does not guarantee that a patient will eat the entire meal or that the patient will not consume additional carbohydrates. An alternative approach is to administer prandial insulin based upon carbohydrate intake. In a retrospective study, the introduction of flexible meal dosing according to carbohydrate intake resulted in an improvement in glycemic control compared with sliding scale alone (8). Carbohydrate counting has shown probable glycemic benefit in outpatients with type 1 diabetes (9), but less clearly in outpatients with type 2 diabetes (10). Unlike hospitalized patients, outpatients are generally otherwise healthy, with good oral intake and recognition of impending hypoglycemia.The Centers for Medicare and Medicaid Services is increasingly emphasizing value-based purchasing decisions (11), recognizing that patient satisfaction is closely linked to clinical quality measures (12). Flexible meal plans are becoming more popular as a means of improving overall patient satisfaction in hospitals (13). A 2008 survey of 270 health care food and nutrition practitioners, suppliers, and manufacturers affiliated with the National Society of Healthcare Foodservice Management reported that 37% of respondents offered restaurant-style room service, with many more planning to make the conversion (13). Such meal plans generally still fall within the prescribed diet order, but it is less clear how this is carried out in practice among patients with diabetes. In patients with diabetes, food choices have received the lowest scores on inpatient diabetes treatment satisfaction questionnaires (14). A flexible meal plan was associated with more hypoglycemia but may improve treatment satisfaction and opportunities for nutrition education (15). Thus, it has become increasingly important to establish glycemic control strategies that address this growing trend.This is the first randomized study to examine the use of prandial insulin dosing according to carbohydrate intake in hospitalized patients.     

规范胰岛素注射部位对2型糖尿病患者血糖的影响

目的 探讨规范胰岛素注射部位对2型糖尿病患者血糖的影响.方法 使用诺和胰岛素的2型糖尿病患者188例,随机分为观察组和对照组各94例.观察组每餐固定胰岛素注射部位:每日注射2次者,早晨进行腹部注射,晚上进行臀部注射;每日注射4次者,早晨和下午进行腹部注射,中午进行上臂注射,睡前进行臀部注射.对照组随机选择注射部位.观察两组患者血糖达标时间.结果 观察组血糖达标时间比对照组短(P=0.00).结论 规范胰岛素注射部位有利于控制2型糖尿病患者血糖,使患者血糖早日达标.     

The Effect of Discontinuing Continuous Glucose Monitoring in Adults With Type 2 Diabetes Treated With Basal Insulin

OBJECTIVETo explore the effect of discontinuing continuous glucose monitoring (CGM) after 8 months of CGM use in adults with type 2 diabetes treated with basal without bolus insulin.RESEARCH DESIGN AND METHODSThis multicenter trial had an initial randomization to either real-time CGM or blood glucose monitoring (BGM) for 8 months followed by 6 months in which the BGM group continued to use BGM (n = 57) and the CGM group was randomly reassigned either to continue CGM (n = 53) or discontinue CGM with resumption of BGM for glucose monitoring (n = 53).RESULTSIn the group that discontinued CGM, mean time in range (TIR) 70–180 mg/dL, which improved from 38% before initiating CGM to 62% after 8 months of CGM, decreased after discontinuing CGM to 50% at 14 months (mean change from 8 to 14 months −12% [95% CI −21% to −3%], P = 0.01). In the group that continued CGM use, little change was found in TIR from 8 to 14 months (baseline 44%, 8 months 56%, 14 months 57%, mean change from 8 to 14 months 1% [95% CI −11% to 12%], P = 0.89). Comparing the two groups at 14 months, the adjusted treatment group difference in mean TIR was −6% (95% CI −16% to 4%, P = 0.20).CONCLUSIONSIn adults with type 2 diabetes treated with basal insulin who had been using real-time CGM for 8 months, discontinuing CGM resulted in a loss of about one-half of the initial gain in TIR that had been achieved during CGM use.     

Effect of Age of Infusion Site and Type of Rapid-Acting Analog on Pharmacodynamic Parameters of Insulin Boluses in Youth With Type 1 Diabetes Receiving Insulin Pump Therapy

OBJECTIVE—The purpose of this study was to examine the effect of type of insulin analog and age of insertion site on the pharmacodynamic characteristics of a standard insulin bolus in youth with type 1 diabetes receiving insulin pump therapy.RESEARCH DESIGN AND METHODS—Seventeen insulin pump–treated adolescents with type 1 diabetes underwent two euglycemic clamp procedures after a 0.2 unit/kg bolus of either insulin aspart or lispro on day 1 and day 4 of insulin pump site insertion. The glucose infusion rate (GIR) required to maintain euglycemia was the primary pharmacodynamic measure.RESULTS—There were no statistically significant differences in any of the pharmacodynamic parameters between aspart and lispro during day 1 and day 4. However, when the two groups were combined, time to discontinuation of exogenous glucose infusion, and time to half-maximal onset and offset of insulin action were observed significantly earlier during day 4 compared with day 1 (P = 0.03–0.0004), but the overall area under the GIR curve was similar on day 1 and day 4.CONCLUSIONS—With both insulin aspart and lispro, there is an earlier peak and shorter duration of action with increasing duration of infusion site use, but overall insulin action is not affected.As a result of the Diabetes Control and Complications Trial and its follow-up Epidemiology of Diabetes Interventions and Complications study, current recommendations mandate that youth with type 1 diabetes should aim to achieve metabolic control as close to normal as possible and as early in the course of the disease as possible. Although such strict treatment goals are particularly difficult to achieve in adolescents with type 1 diabetes (1–3), advances in insulin pump technology and the development of rapid-acting insulin analogs have provided clinicians who treat adolescents with type 1 diabetes with new management tools.With continuous subcutaneous insulin infusion (CSII) pump therapy, bolus doses of rapid-acting insulin analogs provide better control of postprandial hyperglycemia without increasing the risk of hypoglycemia in comparison to what can be achieved with regular insulin (4–9). In addition, the newest insulin pumps account for residual insulin action in their bolus calculator software to prevent hypoglycemia related to multiple bolus doses given over a short interval. However, the duration and decay curves of insulin action programmed into these systems are based on small numbers of adult patients, because the data regarding the pharmacodynamic properties of rapid-acting insulin analogs in CSII-treated youth with type 1 diabetes were not available.Using the euglycemic glucose clamp technique to describe the time-action profile of insulin in adolescents with type 1 diabetes, we recently demonstrated that the peak action of insulin aspart is not observed until 90 min after a standard bolus dose of 0.2 unit/kg, a full 40 min after the peak plasma insulin concentrations are achieved (10). It is important to note that all of these studies were performed in insulin pump–treated patients ∼12 h after insertion of a new infusion set catheter. Surprisingly, the effects of duration of infusion set use on the pharmacodynamic properties of rapid-acting insulin analogs in youth with type 1 diabetes have not been studied. Consequently, the recommendations that patients change their infusion sites every 2–4 days are based primarily on anecdotal reports of increasing glucose variability as the infusion site ages.In this study, we used the glucose clamp technique to determine whether the pharmacodynamic profiles of aspart insulin differed when the same bolus dose of insulin was delivered through the infusion set after 12 h (day 1) and 84 h (day 4) of use. We also examined whether the pharmacodynamic profiles differed whether lispro or aspart was used in CSII.     

格列美脲与胰岛素治疗2型糖尿病81例临床分析

目的:探讨应用格列美脲(万苏平)与胰岛素治疗2型糖尿病(T2DM)的血脂、血红蛋白、血糖临床疗效及安全性。方法:对81例T2DM患者,采用格列美脲与胰岛素治疗2型糖尿病进行临床治疗,观察格列美脲与胰岛素治疗糖尿病患者后其血糖、糖化血红蛋白(HbA1c)及血脂等指标的变化。结果:格列美脲与胰岛素治疗2糖尿病效果显著。结论:格列美脲与胰岛素可作为2型糖尿病患者的备选降糖药物。     

Insulin Sensitivity Is an Important Determinant of Renal Health in Adolescents With Type 2 Diabetes

OBJECTIVE

Diabetic nephropathy (DN) remains the most common cause of end-stage renal disease and is a major cause of mortality in type 2 diabetes. Insulin sensitivity is an important determinant of renal health in adults with type 2 diabetes, but limited data exist in adolescents. We hypothesized that measured insulin sensitivity (glucose infusion rate [GIR]) would be associated with early markers of DN reflected by estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) in adolescents with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Type 2 diabetic (n = 46), obese (n = 29), and lean (n = 19) adolescents (15.1 ± 2.2 years) had GIR measured by hyperinsulinemic-euglycemic clamps. ACR was measured and GFR was estimated by the Bouvet equation (combined creatinine and cystatin C).

RESULTS

Adolescents with type 2 diabetes had significantly lower GIR, and higher eGFR and ACR than obese or lean adolescents. Moreover, 34% of type 2 diabetic adolescents had albuminuria (ACR ≥30 mg/g), and 24% had hyperfiltration (≥135 mL/min/1.73 m²). Stratifying ACR and eGFR into tertiles, adolescents with type 2 diabetes in the highest tertiles of ACR and eGFR had respectively lower GIR than those in the mid and low tertiles, after adjusting for age, sex, Tanner stage, BMI, and HbA_1c (P = 0.02 and P = 0.04). GIR, but not HbA_1c, LDL, or systolic blood pressure, was also associated with eGFR after adjusting for sex and Tanner stage (β ± SE: −2.23 ± 0.87; P = 0.02).

CONCLUSIONS

A significant proportion of adolescents with type 2 diabetes showed evidence of early DN, and insulin sensitivity, rather than HbA_1c, blood pressure, or lipid control, was the strongest determinant of renal health.