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Background: To compare implantable gastric stimulation therapy with a standard diet and behavioral therapy regimen in a group of carefully selected class 2 and 3 obese subjects by evaluating the difference in the percentage of excess weight loss (EWL) between the control and treatment groups. The primary endpoint was the percentage of EWL from baseline to 12 months after randomization. Implantable gastric stimulation has been proposed as a first-line treatment for severely obese patients; however, previous investigations have reported inconclusive results., Methods: A total of 190 subjects were enrolled in this prospective, randomized, placebo-controlled, double-blind, multicenter study. All patients underwent implantation with the implantable gastric stimulator and were randomized to 1 of 2 treatment groups: the control group (stimulation off) or treatment group (stimulation on). The patients were evaluated on a monthly basis. All individuals who enrolled in this study agreed to consume a diet with a 500-kcal/d deficit and to participate in monthly support group meetings., Results: The procedure resulted in no deaths and a low complication rate. The primary endpoint of a difference in weight loss between the treatment and control groups was not met. The control group lost 11.7% +/- 16.9% of excess weight and the treatment group lost 11.8% +/- 17.6% (P = .717) according to an intent-to-treat analysis., Conclusion: Implantable gastric stimulation as a surgical option for the treatment of morbid obesity is a less complex procedure than current bariatric operations. However, the results of the present study do not support its application. Additional research is indicated to understand the physiology and potential benefits of this therapy.

Objective: This double-blind, placebo-controlled, randomized, multicenter, parallel-group study compared the efficacy, safety, and tolerability of Technosphere insulin with Technosphere powder as placebo in insulin-naive type 2 diabetic patients whose diabetes was suboptimally controlled with oral antidiabetic agents., Research Design and Methods: Patients (n = 126) were randomly assigned to 12 weeks of therapy with Technosphere insulin or Technosphere powder after lifestyle education on nutrition, exercise, and instructions on inhaler use. The primary efficacy outcome was change in A1C from baseline to study end, and the secondary efficacy outcome was area under the curve for postprandial glucose levels during a meal test at treatment weeks 4, 8, and 12., Results: A1C reduction from a mean baseline of 7.9% was greater with Technosphere insulin than with Technosphere powder (-0.72 vs. -0.30%; P = 0.003). Postprandial glucose excursions were reduced by 56% with Technosphere insulin compared with baseline, and maximal postprandial glucose levels were reduced by 43% compared with Technosphere powder. Incidences of hypoglycemia, hyperglycemia, cough, and other adverse events were low in both groups. Body weight was unchanged in both groups., Conclusions: Technosphere insulin was well tolerated and demonstrated significant improvement in glycemic control with clinically meaningful reductions in A1C levels and postprandial glucose concentrations after 12 weeks of treatment.

The Coalition for Clinical Research-Self-Monitoring of Blood Glucose Scientific Board, a group of nine academic clinicians and scientists from the United States and Europe, convened in San Francisco, California, on June 11-12, 2008, to discuss the appropriate uses of self-monitoring of blood glucose (SMBG) and the measures necessary to accurately assess the potential benefit of this practice in noninsulin-treated type 2 diabetes mellitus (T2DM). Thirteen consultants from the United States, Europe, and Canada from academia, practice, and government also participated and contributed based on their fields of expertise. These experts represent a range of disciplines that include adult endocrinology, pediatric endocrinology, health education, mathematics, statistics, psychology, nutrition, exercise physiology, and nursing. This coalition was organized by Diabetes Technology Management, Inc. Among the participants, there was consensus that: protocols assessing the performance of SMBG in noninsulin treated T2DM must provide the SMBG intervention subjects with blood glucose (BG) goals and instructions on how to respond to BG data in randomized controlled trials (RCTs);intervention subjects in clinical trials of SMBG-driven interventions must aggressively titrate their therapeutic responses or lifestyle changes in response to hyperglycemia;control subjects in clinical trials of SMBG must be isolated from SMBG-driven interventions and not be contaminated by physician experience with study subjects receiving a SMBG intervention;the best endpoints to measure in a clinical trial of SMBG in T2DM include delta Hemoglobin A1c levels, hyperglycemic events, hypoglycemic events, time to titrate noninsulin therapy to a maximum necessary dosage, and quality of life indices;either individual randomization or cluster randomization may be appropriate methods for separating control subjects from SMBG intervention subjects, provided that precautions are taken to avoid bias and that the sample size is adequate;treatment algorithms for assessing SMBG in T2DM may include a dietary, exercise, and/or medication intervention, which are all titratable according to the SMBG values;the medical literature contains very little information about the performance of SMBG in T2DM from RCTs in which treatment algorithms were used for dysglycemic values; and research on the performance of SMBG in T2DM based on sound scientific principles and clinical practices is needed at this time.

Background: Efforts to mimic euglycemia depend upon targets from epidemiologic studies that rely on episodic measurements reduced to statistical summaries, leaving open the question, "What is normal glycemia?" We postulated that portrayal of euglycemia was possible through application of continuous glucose monitoring (CGM) and a novel analytical tool, the ambulatory glucose profile (AGP)., Methods: Individuals with normal glucose tolerance (NGT) and with diabetes used CGM for 30 days. AGP analysis, which graphs CGM data by time without regard to date, was used to characterize glucose exposure, variability, and stability., Results: Sixty-two subjects completed the study, employing CGM for 28 +/- 4 days averaging 99 +/- 18 (range, 33-125) readings per day. NGT subjects (n = 32) had a mean CGM of 102 +/- 7 mg/dL, ranging between 94 and 117 mg/dL and averaging 105 +/- 8 mg/dL daytime and 97 +/- 6 mg/dL overnight. Glucose variability, as expressed by the interquartile range, was 21 +/- 4 mg/dL (range, 14-29 mg/dL). Stability in glycemic control (hourly change in the median) for NGT subjects averaged 3 +/- 1 mg/dL/h. Subjects with diabetes (n = 30) were significantly higher on all glycemic characteristics with the exception of the percentage of hypoglycemic (CGM <70 mg/dL) episodes for type 2 diabetes (2.9%), compared to 2.7% for subjects with NGT., Conclusions: CGM technologies enabled collection of verified data under normal living conditions, providing an exceptional vantage point from which to obtain important clinical information. This will facilitate an understanding of the range of euglycemic patterns, provide a sensitive means of detecting impaired glucose tolerance, and help set realistic treatment goals for individuals with diabetes.

Hypoglycemia is a potentially serious side effect of blood glucose lowering in diabetes mellitus. The intensive glycemia treatment arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is designed to treat patients with type 2 diabetes with target glycemia within the normal range (ie, glycosylated hemoglobin <6%). Because it is known that treating glycemia to such a low level in patients with diabetes will result in episodes of hypoglycemia, it is necessary to address prevention and treatment of such episodes to ensure patient safety. Thus, several approaches are being taken in the ACCORD trial to prevent initial episodes of severe hypoglycemia, to monitor the frequency of episodes that do occur, and to prevent recurrence. This report describes the processes used in the ACCORD trial, including the definition of severe hypoglycemia, the type of education provided to participants and staff members to prevent initial and subsequent episodes of severe hypoglycemia, and the monitoring systems implemented to identify severe hypoglycemia and prevent its recurrence. The ACCORD trial conducts review and oversight of individual cases of severe hypoglycemia and monitors rates of severe hypoglycemia by clinical site and treatment arm. If the ACCORD intensive glycemia treatment is found to be efficacious in preventing cardiovascular disease events, assessment of the risk and benefit will be essential. In addition, translation of the principles behind the monitoring of severe hypoglycemia in ACCORD into feasible strategies for use in clinical practice will be needed.

Objectives: To construct a novel and clinically relevant means of representing self-monitored blood pressure (SMBP)., Methods: Patients treated to an office blood pressure (BP) < 130/80 mmHg measured their BP at home for 14 days using an Omron IC semi-automatic portable monitor with memory. SMBP data were transferred from the monitor to a computer to produce graphic profiles (SMBPp) that depict the hourly variation in BP throughout a "typical" or modal day., Results: Office BP and SMBP data from 66 subjects with type 2 diabetes and hypertension (HTN), who completed a previous study of intensified management, were analyzed based on European Society of Hypertension-European Society of Cardiology (ESH-ESC) classifications. Patients were classified as Optimal (6), Normal (12), High Normal (15), Isolated systolic HTN (29) and Grades 1, 2 or 3 HTN (4). SMBP disagreed in 32 cases, placing 29 patients in higher risk categories. Analysis by SMBPp of the 33 patients originally classified as Optimal, Normal or High Normal showed that on average 50 +/- 31% of their systolic SMBP values exceeded ESH-ESC thresholds for HTN (135 mmHg). It also revealed that 74 +/- 21% of their SMBP values exceeded the treatment goal (< 25 mmHg) for high-risk patients with type 2 diabetes., Conclusions: SMBPp allowed for a definitive measurement of the dynamic daily BP changes. It produced compelling evidence of persistent patterns of BP fluctuations among patients with normal office BP whose uncontrolled HTN would have remained undetected.

Objective: To determine the safety and efficacy of the long-acting insulin analog, insulin glargine, as a component of basal bolus therapy in patients with type 1 diabetes., Research Design and Methods: Patients with type 1 diabetes receiving basal-bolus insulin treatment with NPH human insulin and insulin lispro were randomized to receive insulin glargine (HOE 901), a long-acting basal insulin analog, once a day (n = 310) or NPH human insulin (n = 309) as basal treatment with continued bolus insulin lispro for 16 weeks in an open-label study NPH insulin patients maintained their prior schedule of administration once or twice a day, whereas insulin glargine patients received basal insulin once a day at bedtime., Results: Compared with all NPH insulin patients, insulin glargine patients had significant decreases in fasting blood glucose measured at home (means +/- SEM, -42.0 +/- 4.7 vs. -12.4 +/- 4.7 mg/dl [-2.33 +/- 0.26 vs. -0.69 +/- 0.26 mmol/l]; P = 0.0001). These differences were evident early and persisted throughout the study More patients in the insulin glargine group (29.6%) than in the NPH group (16.8%) reached a target fasting blood glucose of 119 mg/dl (< 6.6 mmol/l). However, there were no differences between the groups with respect to change in GHb. Insulin glargine treatment was also associated with a significant decrease in the variability of fasting blood glucose values (P = 0.0124). No differences in the occurrence of symptomatic hypoglycemia, including nocturnal hypoglycemia, were observed. Overall, adverse events were similar in the two treatment groups with the exception of injection site pain, which was more common in the insulin glargine group (6.1%) than in the NPH group (0.3%). Weight gain was 0.12 kg in insulin glargine patients and 0.54 kg in NPH insulin patients (P = 0.034)., Conclusions: Basal insulin therapy with insulin glargine once a day appears to be as safe and at least as effective as using NPH insulin once or twice a day in maintaining glycemic control in patients with type 1 diabetes receiving basal-bolus insulin treatment with insulin lispro.

Purpose: This study was conducted to evaluate patients' proficiency in self-monitoring of blood glucose (SMBG)., Methods: Diabetes nurse educators in 4 suburban Minneapolis clinic sites surveyed the SMBG training/cure practices of 280 patients with type 1 and type 2 diabetes. Participant SMBG technique was measured by direct observation. Participants performed a finger puncture and used their own meters to measure the first blood sample. A second sample was measured on the HemoCue B Glucose analyzer, and a third sample was used to measure hemoglobin. The series of tests were then repeated. If either of the 2 glucose tests was more than 15% from the HemoCue value, participants were reeducated about the manufacturer's suggested procedure., Results: Of the 280 participants, 19% had blood glucose test results greater than the 15% limit for meter accuracy. After reeducation, 69% of those who had initially failed achieved acceptable results. The most significant problems were lack of periodic meter technique evaluation, difficulty using wipe meters, incorrect use of control solutions, lack of hand washing even when observed, and unclean meters., Conclusions: As a result of the study, guidelines were subsequently developed to evaluate meter accuracy in an outpatient setting. Further effort is needed to establish standards for evaluating SMBG.

Objective: To assess the effect of medical nutrition therapy (MNT) provided by dietitians on medical and clinical outcomes for adults with non-insulin-dependent diabetes mellitus (NIDDM), and to compare MNT administered according to practice guidelines nutrition care (PGC) to MNT administered with basic nutrition care (BC)., Design: A prospective, randomized, controlled clinical trial of two levels of MNT on metabolic control in persons newly diagnosed with or currently under treatment for NIDDM was conducted at diabetes centers in three states (Minnesota, Florida, and Colorado). BC consisted of a single visit with a dietitian; PGC involved an initial visit with a dietitian followed by two visits during the first 6 weeks of the study period. Data were collected at entry to the study and at 3 and 6 months., Subjects: Results are reported for 179 men and women aged 38 to 76 years: 85 assigned randomly to BC and 94 to PGC. This represents 72% of the 247 subjects enrolled. An additional 62 adults with NIDDM at one site who had no contact with a dietitian were identified as a nonrandom comparison group., Outcomes: Medical outcome measures included fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and serum lipid levels. Clinical outcomes included weight, body mass index, waist-to-hip ratio, and changes in medical therapy., Statistical Analyses: Initial analysis of the discrete variables was done using the chi 2 statistic with Yates' correction. Initial analysis of continuous variables was done by analysis of variance. The changes in variables between time periods were analyzed by paired t test, and comparisons between groups were analyzed using a t test for independent groups., Results: At 6 months, PGC resulted in significant improvements in blood glucose control as indicated by FPG and HbA1c levels and BC resulted in significant improvements in HbA1c level. Participants assigned to the PGC group had a mean FPG level at 6 months that was 10.5% lower than the level at entry, and those in the BC group had a 5.3% lower value. Among subjects who had diabetes for longer than 6 months, those who received PGC had a significantly better HbA1c level at 3 months compared with those receiving BC. The comparison group showed no improvement in glycemic control over a comparable 6 months. PGC subjects had significant improvements in cholesterol values at 6 months, and subjects in both the PGC and the BC groups had significant weight loss., Conclusions: MNT provided by dietitians resulted in significant improvements in medical and clinical outcomes in both the BC and PGC groups and is beneficial to persons with NIDDM. Persons with a duration of diabetes longer than 6 months tended to do better with PGC than with BC. Because of the upward trend in glucose levels after 3 months, ongoing MNT by dietitians is important for long-term metabolic control.

Objective: To conduct a cost analysis and cost-effectiveness study based on a randomized clinical trial of basic nutrition care (BC) and practice guidelines nutrition care (PGC) provided by dietitians in outpatient clinics., Design: Subjects with non-insulin-dependent diabetes mellitus (NIDDM) from three states (Minnesota, Florida, Colorado) were randomly assigned to a group receiving BC or a group receiving PGC for a 6-month clinical trial. Along with data about medical and clinical outcomes, data about cost resources were collected. The cost-effectiveness of PGC compared with BC was calculated using per-patient costs and glycemic outcomes for the 6 months of the study. A net cost-effectiveness ratio comparing BC and PGC, including the cost savings resulting from changes in medical therapy, was also calculated., Subjects: The study reports on a sample of 179 subjects with NIDDM between the ages of 38 and 76 years who completed the clinical trial., Results: Patients in the PGC group experienced a mean 1.1 +/- 2.8 mmol/L decrease in fasting plasma glucose level 6 months after entry to the study, for a total per-patient cost of $112. PGC costs included one glycated hemoglobin assay used by the dietitian to evaluate nutrition outcomes. Patients in the BC group experienced a mean 0.4 +/- 2.7 mmol/L decrease, for a total per-patient cost of $42. In the PGC group, 17 persons had changes in therapy, which yielded an average 12-month cost savings prorated for all patients of $31.49. In contrast, in the BC group, 9 persons had changes in therapy, for an average 12-month prorated cost savings of $3.13. Each unit of change in fasting plasma glucose level from entry to the 6-month follow-up can be achieved with an investment of $5.75 by implementing BC or of $5.84 by implementing PGC. If net costs are considered (per-patient costs--cost savings due to therapy changes), the cost-effectiveness ratios become $5.32 for BC and $4.20 for PGC, assuming the medical changes in therapy were maintained for 12 months., Applications: These findings suggest that individualized nutrition interventions can be delivered by experienced dietitians with a reasonable investment of resources. Cost-effectiveness is enhanced when dietitians are engaged in active decision making about intervention alternatives based on the patient's needs.

The results of the multicenter diabetes control and complications trial are examined and methods for the implementation of the findings for individuals with type I and type II diabetes are discussed. More than a decade ago the question was raised of whether tight glycemic control would prevent or slow the progression of microvascular complications. In 1993, having studied 1441 individuals with type I diabetes randomized to either intensive glycemic control (HbA1c < 7%) or conventional glycemic control (HbA1c > 9%), it was concluded that a reduction in risk of retinopathy, neuropathy and nephropathy could be realized if near normal glycemic control were achieved. Some questions remained, however. For example, could intensive treatment be achieved in routine practice under the auspices of primary care physicians? Are the findings in this study applicable to individuals with type II diabetes? These questions are addressed through the introduction of staged diabetes management (SDM), an innovative approach to the treatment of diabetes and the prevention of its complications. SDM is designed as a data-based systematic approach to diabetes treatment that targets blood glucose control. Studied in 40 clinical sites throughout the United States and evaluated in 30 sites worldwide, SDM promises to provide appropriate clinical guidance to both primary care and specialist physicians seeking to alter current practice patterns by adopting a systematic approach to diabetes management.

We compared counterregulatory metabolic and hormonal responses in 8 normal controls with responses in 16 Type I (insulin-dependent) diabetics, 7 of whom had had repeated attacks of severe hypoglycemia, in an effort to determine whether these responses are related to the occurrence of hypoglycemia in the latter group. In response to insulin-induced hypoglycemia, peak values for glucose production (5.7 +/- 0.5 vs. 2.5 +/- 0.3 mg per kilogram of body weight per minute) (P less than 0.0001), glucagon (195 +/- 26 vs. 93 +/- 18 pg per milliliter) (P less than 0.0001), and growth hormone (63 +/- 8 vs. 37 +/- 5 ng per milliliter) (P less than 0.006) were significantly higher in the controls than in the diabetics. However, peak values for glucose production, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone were similar in the diabetics with and without clinical hypoglycemia. Thus, with the present dose and method of insulin administration we were unable to predict the presence of severe hypoglycemic reactions in a group of Type I diabetics. Although deficient counterregulatory hormone responses are important in the pathogenesis of hypoglycemic reactions, we conclude that other factors in the daily lives of such patients also play a major part in determining whether reactions will occur.

Large quantities of biosynthetic human proinsulin have recently become available through recombinant DNA technology. Since the in vivo effects of human proinsulin have not been studied in man, we compared the dose-response relationship for stimulation of glucose disposal and suppression of hepatic glucose output by proinsulin and insulin. Ten normal subjects were studied using the euglycemic glucose clamp technique. The human proinsulin and insulin infusion rates were chosen to achieve steady-state proinsulin levels 10-fold higher than insulin levels on a molar basis, based on previous observations that porcine proinsulin has approximately 10% the potency of insulin. Proinsulin infusion rates of 2.75, 7.5, 22.5, and 45 micrograms/m2/min were compared with insulin infusion rates of 0.63, 1.67, 5, and 10 micrograms/m2/min. Primed, continuous infusions of insulin yielded steady-state levels within 25 min, whereas proinsulin levels did not reach a steady state for 120-180 min. The metabolic clearance rate of insulin was 11-12 ml/kg/min at the lower infusion rates but fell to 8.4 ml/kg/min at the highest infusion rate. The metabolic clearance rate of proinsulin was 3.0-3.5 ml/kg/min at all infusion rates. Dose-response analysis demonstrated that proinsulin-mediated glucose disposal was approximately 8% that of insulin. In contrast, proinsulin-mediated suppression of hepatic glucose output was approximately 12% that seen with insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the risk and possible mechanisms of hypoglycaemia during moderate exercise in Type I (insulin-dependent) diabetic patients receiving constant insulin infusion, five insulin-dependent male diabetic patients were exercised 18 h after their last meal and 30 h after their last injection of intermediate acting insulin. Intravenous insulin was initially delivered via a closed-loop infusion system programmed to lower mean blood glucose from 11.3 +/- 1.8 to 4.8 +/- 0.4 mmol/l over approximately 3.5 h. Blood glucose was then maintained at this level for 4 h. At this time, the closed-loop infusion was discontinued and replaced by an open-loop system. The average amount of insulin infused per min during the 4 h normoglycaemic closed-loop period was calculated and this amount was infused at a constant rate during both a 30 min period of exercise on a bicycle ergometer (approximately 65% maximum oxygen uptake) and a 30 min rest period which followed. Five nondiabetic males served as control subjects. Despite significantly higher free insulin concentrations (p less than 0.05) and identical pre-exercise blood glucose concentrations, blood glucose rose during exercise only in the diabetic group (0.5 +/- 0.2 mmol/l; p less than 0.01). Changes in the serum concentrations of lactate, glycerol, glucagon, cortisol, non-esterified fatty acids and growth hormone were similar in the two groups and did not account for the increment of blood glucose in the diabetic patients. Beta-hydroxybutyrate concentrations were, however, higher in the diabetic patients at the onset of exercise (p less than 0.01) and decreased significantly more than the control subjects during exercise. We conclude that exercise under these conditions in diabetic patients is not attended by hypoglycaemia.

To assess the effects of pregnancy on the relationships between plasma insulin and proinsulin, studies were performed during late gestation in women with normal carbohydrate metabolism or diabetes mellitus. Plasma was secured after overnight fast and 1, 2, and 3 hours following oral glucose (100 g). Samples were analyzed directly for total immunoreactive insulin (TIR) and for insulin and proinsulin following plasma fractionation by gel filtration. Fractionation disclosed that most of the normal gestational increase in basal and glucose-stimulated TIR can be ascribed to insulin rather than disproportionate increments in proinsulin-like components. Normal proinsulin/insulin relationships were also preserved in mild diabetics despite greater variability in their TIR response to glucose. Thus, mild carbohydrate intolerance during pregnancy is not attended by abnormalities in plasma proinsulin. In contrast basal proinsulin levels were elevated in 4 of 9 pregnant subjects with diabetes sufficiently severe to necessitate subsequent insulin therapy. Following glucose administration in the severe diabetics, the relative contribution from proinsulin to TIR was altered so that ratios of circulating proinsulin/insulin were increased at all levels of blood sugar. Postpartum tests of glucose tolerance in some of the normal and mildly diabetic subjects confirmed that pregnancy per se does not modify appreciably the relationships between plasma insulin and proinsulin although there may be some tendency for proinsulin to account for a smaller proportion of TIR.

An objective of The Kroc Collaborative Study Group trial of the feasibility of maintaining improved control of plasma glucose concentrations with continuous subcutaneous insulin infusion (CSII) was to test the non-glycemic aspects of metabolic control in relation to microvascular disease. Serum lipid levels were assessed in the 68 patients completing the 8-mo trial, before and after randomization to conventional insulin treatment (CIT) or CSII. During CSII, fasting serum cholesterol concentrations, normal at baseline (186 +/- 7 mg/dl), were unchanged at 4 and 8 mo (183 +/- 8 and 186 +/- 10 mg/dl). Fasting serum triglyceride concentrations fell on treatment with CSII (baseline 90 +/- 12 mg/dl, 8 mo 60 +/- 7 mg/dl, P less than 0.01), but were unchanged during CIT (baseline 88 +/- 8 mg/dl, 8 mo 83 +/- 10 mg/dl). Thirty-two patients in three centers had 24-h profiles of intermediary metabolites measured at baseline (0), 4, and 8 mo. Mean 24-h venous blood lactate levels fell during CSII (baseline 1.28 +/- 0.12 mmol/L, 4 mo 0.99 +/- 0.4 mmol/L, P less than 0.05; 8 mo 1.05 +/- 0.11 mmol/L), but blood alanine levels were unchanged. Venous blood 3-hydroxybutyrate fell from 0.12 X /divided by 1.18 mmol/L at baseline to 0.06 X /divided by 1.22 mmol/L at 8 mo during CSII (P less than 0.01), mainly due to decreases at 0400 and 0600 h. Decreases in fasting serum triglyceride levels confirm previous investigations of insulin-dependent diabetic subjects treated with CSII; decreases of venous blood lactate and 3-hydroxybutyrate levels toward normal indicate that these metabolic effects of CSII recognized in short-term studies are sustained over an 8-mo period.