Search

Background: This pilot trial was designed to determine if an optimal dose of Technosphere(®) insulin (TI) inhalation powder (MannKind Corp., Valencia, CA) could be used regardless of variation in meal carbohydrate (CHO) content., Subjects and Methods: In total, eight subjects (seven men, one woman) with type 2 diabetes were enrolled. Subjects underwent dose optimization meal challenge (MC) visits (100% CHO) and MCs with varied CHO meal contents (50%, 200%, and 0% calculated CHOs). Primary end point was change in postprandial glucose (PPG) excursions. Baseline demographics were 60±7 years of age, diabetes duration of 12.3±4.27 years, hemoglobin A1c (A1C) of 7.82±1.04%, and body mass index of 31.3±5.48 kg/m(2)., Results: Maximum mean PPG excursions for the nominal 100% CHO meals were -13±15 mg/dL for breakfast (B) and -14±15 mg/dL for lunch (L), similar to those after 50% CHO meals (B, -17±16 mg/dL; L, +14±10 mg/dL). The largest excursions occurred during 200% CHO meals and remained below American Diabetes Association targets (B, +19±16 mg/dL; L, +32±29 mg/dL). During 15 of the MCs, subjects took their usual TI dose and then had no meal (0% CHO). For the 0% CHO MCs, the largest mean PPG excursion were -33±9 mg/dL at 60 min (B) and -31±10 mg/dL at 60 and 90 min (L). Mean A1C dropped from 7.82±1.04% at the Week 1 visit to 6.18±0.46% (P=0.00091) at the Week 19 visit., Conclusions: Results in eight patients suggest that once an optimal dose of TI is determined, type 2 diabetes patients can ingest meals with a wide range of CHO content or even skip meals without severe hypoglycemia. During this pilot study TI therapy improved A1C by -1.63% (P=0.00091) during 19 weeks of treatment.

As basal insulin analogues are being used off-label, there is a need to evaluate their safety (maternal hypoglycaemia and fetal and perinatal outcomes) and efficacy [haemoglobin A1c(HbA1c), fasting plasma glucose, and maternal weight gain]. The aim of this review is to provide an overview of the current literature concerning basal insulin analogue use in diabetic pregnancy, and to present the design and preliminary, non-validated baseline characteristics of a currently ongoing randomized, controlled, open-label, multicentre, multinational trial comparing insulin detemir with neutral protamine hagedorn insulin, both with insulin aspart, in women with type 1 diabetes planning a pregnancy (n = 306) or are already pregnant (n = 164). Inclusion criteria include type 1 diabetes > 12 months' duration; screening HbA1c ≤ 9.0% (women recruited prepregnancy), or pregnant with gestational age 8-12 weeks and HbA1c ≤ 8.0% at randomization. At confirmation of pregnancy all subjects must have HbA1c ≤ 8.0%. Exclusion criteria include impaired hepatic function, cardiac problems, and uncontrolled hypertension. Subjects are randomized to either insulin detemir or neutral protamine hagedorn insulin, both with prandial insulin aspart. The results are expected mid-2011 with full publications expected later this year. Baseline characteristics show that basal insulin analogues are already frequently used in pregnant women with type 1 diabetes. This study will hopefully elucidate the safety and efficacy of the basal insulin analogue detemir in diabetic pregnancy., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: We compared changes in response to unmasking of continuous glucose monitoring (CGM) in subjects with type 1 diabetes who use multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII)., Research Design and Methods: Use of real-time CGM (DexCom [San Diego, CA] SEVEN was studied in 38 subjects using CSII and 26 using MDI. CGM output was masked during Week 1 and unmasked during Weeks 2 and 3. We evaluated changes in 16 criteria for quality of glycemic control and eight criteria for glycemic variability., Results: All 24 criteria showed highly statistically significant improvement when considered simultaneously (P < 0.000001). For subjects using CSII, 18 of 24 criteria improved significantly (nominal P < 0.05); for subjects using MDI, 16 of 24 criteria improved significantly (P < 0.05). Twelve of the comparisons remained significant (P < 0.05) after applying the overconservative Bonferroni correction for multiple comparisons. The percentage of glucose values within the range 80-140 mg/dL increased by 19% and 17% relative to their control values (Week 1) for subjects using MDI and CSII, respectively. Mean glucose, overall SD (SD(T)), SD between daily means (SD(dm)), mean amplitude of glycemic excursion (MAGE), and mean of daily differences (MODD) improved significantly. Responses to CGM display were not significantly different between the MDI and CSII subject groups for any of the 24 criteria considered individually or in groups of eight, 16, or 24., Conclusion: CGM has similar effectiveness in subjects with type 1 diabetes using either CSII or MDI.

Intensive insulin therapy has an inherent risk of hypoglycemia that can lead to loss of consciousness, cardiac arrhythmia, seizure, and death ("dead-in-bed syndrome"). This risk of hypoglycemia is a major concern for patients, families, and physicians. The need for an automated system that can alert in the event of severe hypoglycemia is evident. In engineering systems, where there is a risk of malfunction of the primary control system, alert and safety mechanisms are implemented in layers of protection. This concept has been adopted in the proposed system that integrates a hypoglycemia prediction algorithm with a global position system (GPS) locator and short message service such that the current glucose value with the rate of change (ROC) and the location of the subject can be communicated to a predefined list. Furthermore, if the system is linked to the insulin pump, it can suspend the pump or decrease the basal insulin infusion rate to prevent the pending event. The system was evaluated on clinical datasets of glucose tracings from the DexCom Seven system. Glucose tracings were analyzed for hypoglycemia events and then a text message was broadcast to a predefined list of people who were notified with the glucose value, ROC, GPS coordinates, and a Google map of the location. In addition to providing a safety layer to a future artificial pancreas, this system also can be easily implemented in current continuous glucose monitors to help provide information and alerts to people with diabetes.

Background: Modern insulin pump therapy for type 1 diabetes mellitus offers the freedom to program several basal profiles that may accommodate diurnal ariability in insulin sensitivity and activity level. However, these basal profiles do not change even if a pending hypoglycemic or hyperglycemic event is foreseen. New insulin pumps could receive a direct feed of glucose values from a continuous glucose monitoring (CGM) system and could enable dynamic basal adaptation to improve glycemic control., Method: The proposed method is a two-step procedure. After the design of an initial basal profile, an adaptation of the basal rate is suggested as a gain multiplier based on the current CGM glucose value and its rate of change (ROC). Taking the glucose value and its ROC as axes, a two-dimensional plane is divided into a nine-zone mosaic, where each zone is given a predefined basal multiplier; for example, a basal multiplier of zero indicates a recommendation to shut off the pump., Results: The proposed therapy was evaluated on 20 in silico subjects (ten adults and ten adolescents) in the Food and Drug Administration-approved UVa/Padova simulator. Compared with conventional basal therapy, the proposed basal adjustment improved the percentage of glucose levels that stayed in the range of 60-180 mg/dl for all 20 subjects. In addition, the adaptive basal therapy reduced the average blood glucose index values., Conclusions: The proposed therapy provides the flexibility to account for insulin sensitivity variations that may result from stress and/or physical activities. Because of its simplicity, the proposed method could be embedded in a chip in a future artificial pancreatic beta cell or used in a "smart" insulin pump., (2009 Diabetes Technology Society.)

Background: This article provides a clinical update using a novel run-to-run algorithm to optimize prandial insulin dosing based on sparse glucose measurements from the previous day's meals. The objective was to use a refined run-to-run algorithm to calculate prandial insulin-to-carbohydrate ratios (I:CHO) for meals of variable carbohydrate content in subjects with type 1 diabetes (T1DM)., Method: The open-labeled, nonrandomized study took place over a 6-week period in a nonprofit research center. Nine subjects with T1DM using continuous subcutaneous insulin infusion participated. Basal insulin rates were optimized using continuous glucose monitoring, with a target fasting blood glucose of 90 mg/dl. Subjects monitored blood glucose concentration at the beginning of the meal and at 60 and 120 minutes after the start of the meal. They were instructed to start meals with blood glucose levels between 70 and 130 mg/dl. Subjects were contacted daily to collect data for the previous 24-hour period and to give them the physician-approved, algorithm-derived I:CHO ratios for the next 24 hours. Subjects calculated the amount of the insulin bolus for each meal based on the corresponding I:CHO and their estimate of the meal's carbohydrate content. One- and 2-hour postprandial glucose concentrations served as the main outcome measures., Results: The mean 1-hour postprandial blood glucose level was 104 +/- 19 mg/dl. The 2-hour postprandial levels (96.5 +/- 18 mg/dl) approached the preprandial levels (90.1 +/- 13 mg/dl)., Conclusions: Run-to-run algorithms are able to improve postprandial blood glucose levels in subjects with T1DM., (2009 Diabetes Technology Society.)

The development of drugs and devices in the treatment of pregnancies complicated by diabetes is in constant forward progression to compensate for pancreatic beta cell insufficiency. Maternal hyperglycemia during pregnancy is of particular interest due to the severe consequences that surface when a fetus is in development. The drugs that are currently recommended for use during pregnancy include rapid-acting insulin analogs lispro and aspart for meal-related bolus insulin and intermediate-acting NPH for basal insulin. Oral anti-diabetic agents are not recommended for use during pregnancy. Better control may be achieved with the incorporation of real-time glucose sensors and new insulin pumps with hopes of improving pregnancy outcome.

Objective: To assess pulmonary safety during discontinuation and readministration of inhaled human insulin (EXU; Exubera((R)) insulin human [rDNA origin]) Inhalation Powder) therapy in adults with type 1 diabetes., Methods: Patients were randomized to receive basal insulin plus either pre-meal EXU (n=290) or a short-acting subcutaneous (SC) insulin (n=290) for 2 years (comparative phase), followed by 6 months of SC insulin (washout) and 6 months of their original therapy (readministration). Highly standardized lung function tests were performed throughout., Results: Small treatment group differences favoring SC insulin in change from baseline forced expiratory volume in 1s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)) occurred early and were non-progressive. These differences resolved during washout and recurred at the same magnitude during readministration. Both groups maintained glycemic control, and hypoglycemic event rates were similar. In the EXU group, insulin antibody (IAb) levels plateaued at 12 months, declined to near baseline levels during washout and increased during readministration to levels observed in the comparative phase., Conclusions: FEV(1) and DL(CO) changes observed during discontinuation and readministration of EXU therapy are consistent with a reversible, non-progressive and non-pathological effect on lung function. EXU readministration is not associated with an augmented IAb response.

Background: Our objective was to use continuous glucose monitoring to derive the optimal basal insulin infusion rates in adults with type 1 diabetes and using continuous subcutaneous insulin infusion (CSII) pumps., Methods: In an effort to mimic euglycemia during the basal state, we used a standard protocol to adjust basal insulin infusion rates in 16 subjects with type 1 diabetes mellitus who were using CSII pumps. All subjects wore Continuous Glucose Monitoring System sensors (CGMS), Medtronic Minimed, Northridge, CA) in order to obtain around-the-clock tracings of their glucose measurements. Subjects were asked to skip meals periodically in order to optimize basal insulin infusion rates, defined as the basal infusion rates that maintained glucose levels in the range of 65-120 mg/dL during the fasting state or between meals., Results: In order to demonstrate improved glycemic control, with blunting of glucose excursion, we compared the baseline CGMS area under the curve (AUC) to the AUC obtained after optimizing the basal insulin dosages. We analyzed the curves by determining the AUC for glucose excursions above 110 mg/dL. The AUC for glucose excursions above 110 mg/dL was significantly smaller after optimization (19 +/- 13 mg/dL.day) compared to the baseline AUC (50 +/- 31 mg/dL.day) (P < 0.001)., Conclusions: Using both a standard protocol for initial basal insulin infusion rates and CGMS curves to optimize basal infusion rates, one can improve glycemia in subjects with type 1 diabetes using CSII.

Aim: The efficacy and safety of insulin aspart (IAsp), a rapid-acting human insulin analogue, were compared with regular human insulin (HI) as the bolus component of basal-bolus therapy for subjects with gestational diabetes mellitus (GDM)., Methods: In a randomized, parallel-group, open-labelled trial, 27 women with GDM (age 30.7 +/- 6.3 years, HbA(1c) < 7%) were randomized to receive IAsp (5 min before meal) or HI (30 min before meal). The trial period extended from diagnosis of GDM (18-28 weeks) to 6 weeks postpartum., Results: Both treatment groups maintained good overall glycaemic control during the study (beginning and end of study HbA(1c)< or = 6%). During the meal test, mean glucose at week 6 (IAsp 4.2 +/- 0.57 mmol/l, HI 4.8 +/- 0.86 mmol/l) was slightly lower than at week 0 (IAsp 4.9 +/- 0.59 mmol/l, HI 5.1 +/- 0.36 mmol/l). However, change from baseline values for average glucose (IAsp -1.09 +/- 0.54 mmol/l, HI -0.54 +/- 0.74 mmol/l; P = 0.003) and C-peptide (IAsp -0.50 +/- 0.67 nmol/l, HI -0.30 +/- 0.70 nmol/l; P = 0.027) were significantly lower after IAsp treatment than HI treatment. No major hypoglycaemic events were reported during the study. Cross-reacting insulin antibody binding increased slightly from baseline in both treatments groups (end of study: IAsp 2.1 +/- 5.4%, HI 6.4 +/- 13.9%), whereas antibodies specific to IAsp or HI remained relatively low (< 1% binding)., Conclusion: IAsp was more effective than HI in decreasing postprandial glucose concentrations. Duration of IAsp injection 5 min before a meal rather than 30 min prior to meals offers a more convenient therapy for subjects with GDM. Overall safety and effectiveness of IAsp were comparable to HI in pregnant women with GDM.

This review reports the literature on the safety and efficacy of insulin analogues in pregnancy and thereby enables the clinician to choose the optimal insulin treatment protocol to achieve and maintain normoglycemia throughout pregnancies complicated by diabetes. This article also reviews the literature on the insulin analog during pregnancy and presents the authors' opinion as to the safety and efficacy of insulin analog treatment for the pregnant diabetic woman.

Thiazolidinediones have gained widespread use for the treatment of type 2 diabetes mellitus and other insulin resistance states, including polycystic ovary syndrome (PCOS). In thiazolidinedione-treated patients a small reduction in hemoglobin and hematocrit levels often is observed, and this generally has been attributed to fluid retention. Because testosterone is a hematopoietic hormone, we investigated whether a reduction in plasma free testosterone concentration was associated with the decrease in hemoglobin and hematocrit levels in 22 nondiabetic women (9 with normal glucose tolerance and 13 with impaired glucose tolerance; mean age, 29 +/- 5 years; mean body mass index, 35.6 +/- 5.8 kg/m2) with PCOS who were treated with pioglitazone, 45 mg/d. Before treatment and after 4 months, subjects underwent an oral glucose tolerance test and measurement of total body water content with bioimpedance. Plasma testosterone, androstenedione, dehydroepiandrosterone sulfate, hemoglobin, and hematocrit levels were evaluated at baseline and every month for 4 months. The fasting plasma glucose concentration (98 +/- 9 mg/dL) was unchanged after pioglitazone treatment, whereas the 2-hour plasma glucose concentration declined from 146 +/- 41 to 119 +/- 20 mg/dL (P = .002). Both the free androgen index and the free testosterone levels calculated according to Vermeulen et al decreased significantly (from 14.4 +/- 7.1 to 10.6 +/- 7.8 [P = .02] and from 59.4 +/- 23.4 to 46.6 +/- 23.3 [P = .03], respectively). The plasma androstenedione level declined from 259 +/- 134 to 190 +/- 109 ng/dL (P = .01), whereas the dehydroepiandrosterone sulfate level did not change significantly (from 139 +/- 90 to 127 +/- 84 mug/dL, P = .2 [not significant]). The levels of both hemoglobin (from 13.6 +/- 1.0 to 12.8 +/- 1.1 g/dL, P = .0002) and hematocrit (from 39.7% +/- 2.2% to 37.9% +/- 2.7%, P = .002) fell slightly after 4 months of pioglitazone administration. Collectively, before and after pioglitazone administration, the plasma free testosterone level according to Vermeulen et al correlated positively with the levels of hemoglobin (r = 0.49, P < .0001) and hematocrit (r = 0.40, P < .0001), as well as the free androgen index (r = 0.38 [P < .0003] with hemoglobin and r = 0.29 [P < .006] with hematocrit); the decrement in plasma free testosterone level and free androgen index also correlated with the decrements in the levels of both hemoglobin (r = 0.51 [P = .01] and r = 0.54 [P = .01], respectively) and hematocrit (r = 0.42 [P = .05] and r = 0.50 [P = .02], respectively). Body weight increased from 90.5 +/- 17.3 to 92.4 +/- 18.8 kg after pioglitazone administration (P = .05), as did body fat content (from 42.7 +/- 15.3 to 44.8 +/- 17.1 kg, P = .03), which could explain the increase in weight, because edema did not develop in any of the subjects. Total body water content did not change significantly after pioglitazone administration (from 37.7 +/- 5.0 to 37.8 +/- 4.9 L, P = .68 [not significant]). In summary, pioglitazone treatment is associated with a mild decline in hematocrit or hemoglobin level, which is correlated with the reduction in plasma testosterone level. These results suggest that increased body water content cannot explain the reduction in hematocrit or hemoglobin level in women with PCOS. Further studies are necessary to evaluate whether the same scenario is applicable to normoandrogenic women and individuals with type 2 diabetes mellitus.

Aim: To determine the rate of major congenital anomalies in offspring of a large group of women with diabetes mellitus treated with insulin lispro (Humalog)., Methods: This multinational, multicentre, retrospective study included mothers with diabetes mellitus (diagnosed prior to conception) who were treated with insulin lispro for at least 1 month before conception and during at least the first trimester of pregnancy. Anomalies were assessed by two independent dysmorphologists not affiliated with the sponsor., Results: The charts of 496 women were reviewed for 533 pregnancies resulting in 542 offspring (500 live births, 31 spontaneous and seven elective abortions, and four stillbirths). Mothers' characteristics: mean (+/- SD) age was 29.9 (+/- 5.2) years, 85.6% were Caucasian and 97.2% had Type 1 diabetes mellitus. Insulin lispro continued to be the main mealtime insulin for more than 96% of the women during the second and third trimester. The dysmorphologists determined that 27 (5.4%) offspring had major congenital anomalies and 2 (0.4%) offspring had minor congenital anomalies., Conclusions: The rate of major congenital anomalies was 5.4% [95% CI (3.45%, 7.44%)] for offspring of mothers with diabetes mellitus treated with insulin lispro before and during pregnancy. The current published rates of major anomalies in infants born to mothers with diabetes treated with insulin are between 2.1 and 10.9%. This suggests that the anomaly rate with insulin lispro treatment does not differ from the published major congenital anomaly rates for other insulin treatments.

Objective: To examine the effect of short-term improvements in glycaemic control on brachial artery endothelial function as a marker of cardiovascular health., Methods: Persons with Type 2 diabetes who were poorly controlled on oral therapy were randomly assigned to monotherapy with repaglinide or combination therapy with repaglinide plus metformin. Brachial artery flow-mediated vasodilation was assessed by ultrasonography at randomization and following 16 weeks of therapy. The primary outcome was change in brachial artery endothelial function from baseline. Comparison of randomized groups was a secondary aim., Results: Eighty-six participants were randomized, and 83 were followed to study completion. Post occlusion brachial artery vasodilation was 3.74% at baseline and 3.82% following 16 weeks of therapy (P = 0.77). The treatment effect was 0.08% (95% CI: -0.48%, 0.64%). No difference was seen between treatment groups (P = 0.69). Overall, A1C was reduced from 8.3% to 7.0%, with a greater reduction in the combination therapy group (from 8.4% to 6.7%) than in the monotherapy group (from 8.3% to 7.3%, p for difference between groups = 0.01). Statistically significant reductions were observed in fasting glucose, and plasminogen activator inhibitor-1. Statistically significant increases were observed for fasting insulin, uric acid, weight and BMI., Conclusions: Brachial artery endothelial function was not influenced by short-term improvements in glycaemic control. The CONTROL DM group was successful in lowering A1C. Future research should explore more intensive and longer-lasting improvements in glycaemic control on endothelial function. Some data previously published in abstract form (Diabetes 2001; 50 (Suppl. 2): A217).

Background: Patients with type 1 diabetes mellitus (DM) may encounter situations in which meal size and content is unpredictable. In theory, postprandial injection of rapid-acting insulin analogues could prove more effective in achieving glucose control at such times because this treatment strategy could allow adjustment of insulin dose for the actual size of the meal consumed rather than being based on an estimate of what will be consumed., Objective: This study compared the postprandial glycemic control achieved with meal-related insulin aspart injected immediately before a meal with that injected immediately after a meal., Methods: This randomized, crossover study was conducted at Sansum Diabetes Research Institute, Santa Barbara, California. Adult patients with type 1 DM were enrolled. At study visit 1, patients were randomly assigned to inject insulin aspart 0 to 5 minutes before the start of the meal or immediately after the meal. The timing of injection relative to the meal was reversed at study visit 2. The meal-related dose was calculated based on the anticipated caloric and carbohydrate intake (preprandial injection) or actual calories and carbohydrates ingested (postprandial injection). Postprandial blood glucose concentrations were evaluated as markers of efficacy of postprandial aspart administration., Results: Twenty patients were enrolled in the study (mean [SE] duration of DM, 22.5 [3.2] years; mean [SE] body mass index, 26.2 [1.0] kg/M2; age range, 22-82 years); 19 completed it. Total glucose AUC during the meal test was 22% less when insulin aspart was injected immediately before the study meal (mean [SE], 23,014 [1832] mg/dL.min) than when injected immediately after the meal (mean [SE], 29,535 [2243] mg/dL.min) (P < 0.001), but baseline-adjusted AUC was similar. Maximum mean (SD) glucose concentrations in the postprandial period were <180 mg/dL, the current DM treatment goals specified by the American Diabetes Association (149.0 [9.9] mg/dL and 102.0 [9.2] mg/dL, following postprandial insulin aspart injection and preprandial injection, respectively; P < 0.001). There was variation in the number of calories consumed, but patients consumed a similar number of calories in the 2 treatment regimens. The frequency of postprandial hypoglycemia was comparable. Adjustment of postprandial insulin aspart dose for the actual meal size consumed maintained postprandial glucose concentrations within currently recommended treatment guidelines., Conclusions: Preprandial insulin aspart injection produced a better glucose profile and is preferred when conditions permit. However, both preprandial and postprandial insulin aspart administration achieved postprandial glucose concentrations within currently recommended treatment guidelines.

Objective: To present protocols for maintaining normoglycemia during labor and delivery in order to achieve optimal outcomes of pregnancy in women with diabetes., Results: Labor has a glucose-lowering effect. In the case of women with insulin-requiring gestational diabetes, no additional insulin is needed with the onset of labor; sufficient glucose should be infused to keep such women from becoming ketotic from the pronged period of starvation. Likewise, protocols derived from glucose-controlled insulin infusion studies reveal that women with type 1 diabetes require no more subcutaneously administered insulin on the morning of an induction of labor or at the onset of spontaneous labor. The intravenously administered solutions should be started with isotonic saline or electrolyte solutions. As soon as active labor is achieved, the solutions should be switched to a glucose-containing fluid and administered at a rate of 2.55 mg/kg per minute., Conclusion: Labor is a form of exercise and thus obviates the insulin requirement in women with all types of diabetes, but it also necessitates an eightfold increase in glucose substrate in order to prevent maternal hypoglycemia and ketosis. The literature presents clear evidence that neonatal hypoglycemia is directly related to maternal hyperglycemia during labor and delivery. Thus, protocols for maintaining normoglycemia during labor and delivery are necessary to achieve optimal results.

The efficacy and safety of combination therapy (repaglinide plus pioglitazone) was compared to repaglinide or pioglitazone in 24-week treatment of type 2 diabetes. This randomized, multicenter, open-label, parallel-group study enrolled 246 adults (age 24-85) who had shown inadequate response in previous sulfonylurea or metformin monotherapy (HbA(1c) > 7%). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, pioglitazone, or repaglinide/pioglitazone. In the first 12 weeks of treatment, repaglinide doses were optimized, followed by 12 weeks of maintenance therapy. Pioglitazone dosage was fixed at 30 mg per day. Baseline HbA(1c) values were comparable (9.0% for repaglinide, 9.1% for pioglitazone, 9.3% for combination). Mean changes in HbA(1c) values at the end of treatment were -1.76% for repaglinide/pioglitazone, -0.18% for repaglinide, +0.32% for pioglitazone. Fasting plasma glucose reductions were -82 mg/dl for combination therapy, -34 mg/dl for repaglinide, -18 mg/dl for pioglitazone. Minor hypoglycemia occurred in 5% of patients for the combination, 8% for repaglinide, and 3% for pioglitazone. Weight gains for combination therapy were correlated to individual HbA(1c) reductions. In summary, for patients who had previously failed oral antidiabetic monotherapy, the combination repaglinide/pioglitazone had acceptable safety, with greater reductions of glycemic parameters than therapy using either agent alone.

Objective: To assess the short-term efficacy of insulin aspart in comparison with regular human insulin in women with gestational diabetes mellitus (GDM) during standardized meal tests., Research Design and Methods: The study included 15 women with GDM who had inadequate diabetes control with diet alone. On 3 consecutive days, breakfast meal tests were performed-the first with no exogenous insulin and the other two after the injection of either regular insulin or insulin aspart., Results: The peak insulin concentration was higher and the peak glucose and C-peptide concentrations were lower with both insulin preparations than with no exogenous insulin. Glucose areas under the curve above baseline were significantly lower with insulin aspart (180-min area, 7.1 mg. h. dl(-1); P = 0.018), but not with regular insulin (30.2 mg. h. dl(-1); P = 0.997), than with no insulin (29.4 mg. h. dl(-1))., Conclusions: This study demonstrates that effective postprandial glycemic control in women with GDM who required insulin was brought about by insulin aspart through higher insulin peak and lower demand on endogenous insulin secretion.

Objective: This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone., Research Design and Methods: Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured., Results: The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups., Conclusions: Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.

Objective: To compare long-term glycemic control and safety of using insulin aspart (IAsp) with that of regular human insulin (HI)., Research Design and Methods: This was a multicenter randomized open-label 6-month study (882 subjects) with a 6-month extension period (714 subjects) that enrolled subjects with type 1 diabetes. Subjects administered IAsp immediately before meals or regular HI 30 min before meals; basal NPH insulin was taken as a single bedtime dose in the majority of subjects. Glycemic control was assessed with HbA1c values and 8-point blood glucose profiles at 3-month intervals., Results: Mean postprandial blood glucose levels (mg/dl +/- SEM) were significantly lower for subjects in the IAsp group compared with subjects in the HI group after breakfast (156 +/- 3.4 vs. 185 +/- 4.7), lunch (137 +/- 3.1 vs. 162 +/- 4.1), and dinner (153 +/- 3.1 vs. 168 +/- 4.1), when assessed after 6 months of treatment. Mean HbA1c values (% +/- SEM) were slightly, but significantly, lower for the IAsp group (7.78% +/- 0.03) than for the regular HI group (7.93% +/- 0.05, P = 0.005) at 6 months. Similar postprandial blood glucose and HbA1c values were observed at 12 months. Adverse events and overall hypoglycemic episodes were similar for both treatment groups., Conclusions: Postprandial glycemic control was significantly better with IAsp compared with HI after 6 and 12 months of treatment. The improvement was not obtained at an increased risk of hypoglycemia. HbA1c was slightly, but significantly, lower for IAsp compared with HI at 6 and 12 months.

In this 24-week multicenter, double-blind, randomized, fixed-dose trial, 361 patients having type 2 diabetes received daily preprandial treatment with placebo (n = 75), repaglinide 1 mg (n = 140), or repaglinide 4 mg (n = 146). By a last-observation carried-forward calculation, repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose (FPG) values (by -47 mg/dL or -49 mg/dL) while the placebo group had increased FPG values (by 19 mg/dL). For the repaglinide treatment groups at the end of the study, changes in HbA1c from baseline values ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no events of severe hypoglycemia. Nearly all hypoglycemic symptom episodes had blood glucose levels above 45 mg/dL. Repaglinide was well tolerated in a preprandial fixed-dose regimen of 1 mg or 4 mg, assigned without adjustment for clinical parameters.

Objective: To discuss the new criteria for screening and diagnosis of gestational diabetes and present recommendations for patient management., Methods: Various strategies for detecting gestational diabetes historically and currently are reviewed, and approaches for optimizing patient and neonatal outcome are discussed., Results: Rather than testing for gestational diabetes selectively, universal screening of pregnant women between 24 and 28 weeks of gestation with use of a glucose challenge test and 1-hour assessment has been shown to decrease the rate of occurrence of neonatal macrosomia. Performance of both preprandial and postprandial self-monitoring of blood glucose levels helps to prevent pronounced postprandial glucose excursions and minimize the risk of neonatal macrosomia. In comparison with regular human insulin, insulin lispro has yielded significantly better metabolic control and a reduction in hypoglycemic episodes before breakfast in patients with gestational diabetes., Conclusion: Women with gestational diabetes who are not optimally managed with diet and exercise need insulin therapy. Insulin lispro is associated with fewer hypoglycemic events and attenuates the postprandial response greater than does regular human insulin.

Objective: To compare the immunologic response to insulin lispro with that to regular human insulin, thereby assuring its safety for use in women with gestational diabetes, and to verify that it is effective., Research Design and Methods: We compared the metabolic and immunologic effects of insulin lispro and regular human insulin in 42 women >18 years of age diagnosed with gestational diabetes by oral glucose tolerance testing at 14-32 weeks of gestation. Patients were randomized to receive regular human insulin or insulin lispro before consuming a test meal. Serum insulin, blood glucose, and C-peptide concentrations were measured. Throughout the remainder of gestation, patients received premeal insulin lispro or regular human insulin combined with basal insulin and performed blood glucose self-monitoring before and after each meal. Insulin antibodies and HbA1c were determined at enrollment and 6 weeks later. In addition, 10 patients received continuous intravenous insulin (4 lispro, 6 regular human insulin) and dextrose infusions intrapartum to assess placental insulin transfer., Results: Anti-insulin antibody levels were similar in the two groups. Insulin lispro was not detectable in the cord blood. During a meal test, areas under the curve for glucose, insulin, and C-peptide were significantly lower in the lispro group. Mean fasting and postprandial glucose concentrations and end point HbA1c were similar in the two groups. The lispro group demonstrated fewer hypoglycemic episodes (symptoms and blood glucose concentrations <55 mg/dl). No fetal or neonatal abnormalities were noted in either treatment group., Conclusions: Insulin lispro may be considered a treatment option for women with gestational diabetes.

This multicenter, randomized, placebo-controlled study of glimepiride, a new oral sulfonylurea, was conducted in patients with type 2 diabetes for whom dietary treatment was unsuccessful (fasting plasma glucose [FPG] = 151-300 mg/dL) during a 1-week screening period. Patients were randomized to receive glimepiride (n = 123) or placebo (n = 126) once daily for a 10-week dose-titration period, then maintained on an individually determined optimal dose (1-8 mg of glimepiride or placebo) for 12 weeks. Glimepiride lowered FPG by 46 mg/dL, hemoglobin A1C (HbA1C) by 1.4%, and 2-hour postprandial glucose by 72 mg/dL more than placebo. Glimepiride improved postprandial insulin and C-peptide responses without producing clinically meaningful increases in fasting insulin or C-peptide levels. Good glycemic control (HbA1C < or = 7.2%) was achieved by 69% of the patients taking glimepiride versus 32% of those taking placebo. The overall incidence of adverse events was similar in both groups. No clinically noteworthy abnormal laboratory values or hypoglycemia (blood glucose < 60 mg/dL) occurred. Glimepiride is safe and effective for treatment of patients with type 2 diabetes for whom diet therapy is unsuccessful.

This study presents the first multiday therapy trial of linogliride fumarate, a representative of a new class of oral hypoglycemic agents. Linogliride demonstrated a significant hypoglycemic activity in 26 patients with non-insulin-dependent diabetes mellitus receiving 1 week of therapy. In a dose range of 150 to 400 mg b.i.d., fasting glucose levels fell from 237 +/- 52 mg to 199 +/- 59 mg by day 7 (P less than 0.01). Eight-hour glucose AUCs fell from 2121 +/- 617 mg/dl/8 hr baseline to 1781 +/- 631 mg/dl/8 hr on day 7 of treatment (P less than 0.01). This was associated with a significant increase in insulin AUC from 380 +/- 327 to 610 +/- 417 on day 7 (P less than 0.01). Thus its initial action appears to be by an insulin secretagogue mechanism. No patient had any major adverse effect. This initial study indicates that linogliride fumarate is an effective hypoglycemic agent that significantly lowers fasting and postprandial glucose levels with short-term use. Linogliride fumarate represents a new group of hypoglycemic agents that may be shown to have therapeutic utility.

PurposeWe examined the relationship between glycemic control and urinary tract infections in women with type 1 diabetes mellitus.Materials and methodsWomen enrolled in the Epidemiology of Diabetes Interventions and Complications study, the observational followup of the Diabetes Control and Complications Trial, were surveyed to assess the rate of physician diagnosed urinary tract infections in the preceding 12 months. The relationship between glycated hemoglobin levels and number of urinary tract infections in the previous 12 months was assessed using a multivariable Poisson regression model.ResultsA total of 572 women were evaluated at year 17. Mean age was 50.7 ± 7.2 years, mean body mass index was 28.6 ± 5.9 kg/m(2), mean type 1 diabetes duration was 29.8 ± 5.0 years and mean glycated hemoglobin was 8.0% ± 0.9%. Of these women 86 (15.0%) reported at least 1 physician diagnosed urinary tract infection during the last 12 months. Higher glycated hemoglobin levels were significantly associated with number of urinary tract infections such that for every unit increase (1%) in recent glycated hemoglobin level, there was a 21% (p=0.02) increase in urinary tract infection frequency in the previous 12 months after adjusting for race, hysterectomy status, urinary incontinence, sexual activity in the last 12 months, peripheral and autonomic neuropathy, and nephropathy.ConclusionsThe frequency of urinary tract infections increases with poor glycemic control in women with type 1 diabetes. This relationship is independent of other well described predictors of urinary tract infections and suggests that factors directly related to glycemic control may influence the risk of lower urinary tract infections.