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Objective To compare glycemic efficacy of Technosphere insulin (TI) versus that of insulin aspart (IA), each added to basal insulin, in type 2 diabetes. Methods This randomized, 24-week trial included subjects aged from 18 to 80 years who were treated with subcutaneous insulin for 3 months and had glycated hemoglobin (HbA1C) levels of 7.0% to 11.5%. After receiving stabilized insulin glargine doses during a 4-week lead in, the subjects were randomized to TI or IA. The primary end point was an HbA1C change from baseline, with the differences analyzed by equivalence analyses. Results In the overall cohort (N = 309; males, 23.3%), mean (SD) age was 58.5 (8.4) years, body mass index was 30.8 (4.7) kg/m2, weight was 82.2 (13.6) kg, and duration of diabetes was 12.2 (7.1) years. An intention-to-treat cohort had 150 subjects randomized to TI (mean [SD] HbA1C: 8.9% [1.1%]) and 154 randomized to IA (mean [SD] HbA1C: 9.0% [1.3%]). At 24 weeks, mean (SD) HbA1C value declined to 7.9% (1.3%) and 7.7% (1.1%) in the TI and IA cohorts, respectively. A treatment difference of 0.26% was not statistically significant, but the predefined equivalency margin was not met. Subjects receiving TI lost 0.78 kg compared to baseline; subjects receiving IA gained 0.23 kg (P =.0007). The incidence of mild/moderate hypoglycemia was lower for the TI cohort, though not statistically significant. Conclusion Both TI and IA resulted in significant and clinically meaningful HbA1C reductions. TI also resulted in significant and clinically meaningful weight reductions. These data support the use of inhaled insulin as a treatment option for individuals with type 2 diabetes.

Background and Objective Technosphere® Insulin (TI), a human insulin powder for inhalation (Afrezza®; MannKind Corporation, Westlake Village, CA, USA), is an ultra-rapid-acting inhaled insulin indicated to improve postprandial glycemic control in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Because TI is absorbed across the alveolar membrane, the objective of this analysis was to characterize its pulmonary safety. Methods Pooled data from 13 phase 2/3 clinical studies in 5505 patients with T1DM or T2DM treated with TI, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events (TEAEs), changes in pulmonary function, and lung malignancies. Radiographic changes in the lungs were monitored in a subset of 229 patients. Results Among 3017 patients receiving TI, the median duration of TI exposure was 168 days; median active-comparator and TP exposure durations were 363 and 149 days for 2198 and 290 patients, respectively. Respiratory TEAEs were comparable across treatments, except for a higher incidence of mild cough with TI in active-comparator studies (28.0% vs. 5.2%). Slight reversible declines in pulmonary function from baseline were observed for TI versus TP and active-comparator treatments, including in a subpopulation of patients with retrospectively identified lung dysfunction. Lung malignancies were reported in two patients on active TI therapy with a smoking history. No clinically significant changes from baseline were observed in radiographic images. Conclusions Pulmonary safety assessment of the TI inhalation system did not identify any safety issues in individuals with either T1DM or T2DM. Electronic supplementary material The online version of this article (10.1007/s40261-020-00958-8) contains supplementary material, which is available to authorized users.

Dasiglucagon is a novel glucagon analog, stable in aqueous solution and suitable for delivery in a ready-to-use autoinjector (HypoPal®) for the treatment of severe hypoglycemia. This study was performed to assess HypoPal device handling vs. GEK during simulated episodes of severe hypoglycemia. Participants included persons with diabetes (PWD) and their caregivers and untrained bystanders (UB) with no experience with diabetes. Participants had no experience with either device. PWD were trained by staff and subsequently trained caregivers (TC) on the use of devices; UB received no instruction on use prior to simulations. Primary outcome was success of TC to correctly use HypoPal vs. GEK. Secondary outcomes included success of UB, time to successful administration, and assessment of confidence in, ease of use of and preference for each device. The success rate was significantly greater for HypoPal vs. GEK in TC (p These data support that dasiglucagon HypoPal use is easier, more reliable, and faster than the use of GEK and offers the potential to improve the time to recovery from a severe hypoglycemic event. Disclosure N. Bailey: Research Support; Spouse/Partner; Zealand Pharma A/S. J. Dimsits: Employee; Self; Zealand Pharma A/S. R. Tehranchi: Employee; Self; Zealand Pharma A/S. D. M. Kendall: Employee; Self; Zealand Pharma A/S, Employee; Spouse/Partner; Amgen Inc., Stock/Shareholder; Self; Eli Lilly and Company, MannKind Corporation. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. Funding Zealand Pharma A/S

In a recent study (STAT, NCT03143816), patients with type 1 diabetes mellitus (T1DM) treated with Technosphere Insulin (TI) demonstrated better early postprandial glucose (PPG) control than those on subcutaneous (SC) insulin aspart. The average daily dose of TI in patients who took TI as directed in the protocol was twice that of aspart (40.5 vs. 20.6 units). Despite the higher dose, the TI group experienced less time in hypoglycemia than the aspart group. These results prompted a retrospective analysis of mixed-meal tolerance tests (MMTTs) conducted in T1DM to further evaluate the 2:1 dosing ratio. In study MKC-TI-009 (NCT00308308), patients with T1DM underwent 1 to 3 MMTTs. A total of 1326 PPG profiles were evaluable: 674 MMTTs from 261 patients on SC aspart and 652 MMTTs from 264 patients on TI. On average, the area under the PPG excursion curve (PPGE AUC) decreased with increasing dose, and the mean (SE) ratio of the aspart slope to the TI slope was 2.1 (0.3), consistent with the results of STAT. This was confirmed when doses of TI 8, 16, and 24 units were compared with mean (SE) aspart doses of 4 (1), 8 (1), and 12 (1) units, respectively (Figure). The PPGE curves confirm the earlier onset and shorter duration of TI, while the tendency to drop below baseline in the late postprandial period reflects the longer duration of action of SC aspart. The timing of hypoglycemia (levels 1 and 2) follows the pattern of PPGEs. Disclosure M.L. Grant: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. F. Pompilio: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Amgen Inc., MannKind Corporation. G. Sharma: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; Eli Lilly and Company, MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. D.M. Kendall: Employee; Spouse/Partner; Amgen Inc. Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. N. Zaveri: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Becton, Dickinson and Company. Funding MannKind Corporation

Introduction Although depression is often associated with poor glycemic control in patients with type 2 diabetes mellitus (T2DM), this observation has been inconsistent. This exploratory, post hoc analysis investigated associations between depression parameters and glycemic control using data from a 24-month, prospective, observational, non-interventional study evaluating glycemic response following insulin initiation for T2DM. Methods We analyzed data from a 24-month, prospective, observational study that evaluated glycemic response in patients with T2DM who initiated insulin therapy (N = 985) in 5 European countries. Secondary measures included patient-reported diagnosis of depression at baseline, severity of depressed/anxious mood (EuroQol (EQ)-5D item) and diabetes-related distress (Psychological Distress domain of the Diabetes Health Profile, DHP-18). The latter two measures were assessed at baseline and 5 time points throughout the study. Glycemic control was measured by glycated hemoglobin (HbA1c) at these same time points. Analyses employed t tests to assess the unadjusted baseline difference in HbA1c between patients with and without the respective depression parameter. The potential effect of demographic and clinical confounding variables was controlled through a linear model structure. Patient HbA1c levels were analyzed by presence/absence of a history of diagnosed depression, depressed mood, and diabetes-related distress. Results Patients with higher depression parameters or distress at baseline had significantly higher rates of microvascular complications at baseline. Patients with a history of diagnosed depression or high diabetes-related distress had higher HbA1c than patients without. HbA1c of patients with or without depressed mood was not significantly different at baseline. The proportion of patients with depressed mood declined after insulin initiation, whereas the proportion of patients with high diabetes-related distress did not significantly change. HbA1c improved following insulin initiation, regardless of presence/absence of studied depression/distress parameters at baseline. Conclusion History of diagnosed depression, diabetes-related distress, and depressed mood were associated with a higher rate of microvascular complications. Diagnosed depression and diabetes-related distress also showed higher HbA1c at baseline when insulin was initiated. Insulin therapy improved glycemic control, while preexisting depressed mood declined and diabetes-related distress remained unchanged. Electronic supplementary material The online version of this article (doi:10.1007/s13300-015-0118-y) contains supplementary material, which is available to authorized users.

Purpose Although diabetes is recognized as a risk factor for the development of cognitive impairment and for accelerated progression to Alzheimer disease (AD), it is unclear whether patients with diabetes who have already progressed to AD have a different rate of cognitive and functional decline compared with that in those without diabetes. This post hoc exploratory analysis compared cognitive and functional decline over an 18-month period in patients with mild AD dementia with and without comorbid diabetes. Decline in quality of life was assessed as a secondary objective. Methods In a post hoc exploratory analysis, we analyzed data from the placebo groups of three 18-month, randomized, placebo-controlled trials of solanezumab and semagacestat in patients with AD. Data from patients with mild AD dementia (Mini-Mental State Examination [MMSE] score, 20–26) and comorbid diabetes at baseline were compared with data from patients with mild AD dementia without diabetes at baseline. Cognition was assessed using the 14-item AD Assessment Scale–Cognitive Subscale (ADAS-Cog 14 ) and the MMSE. Functioning was assessed with the AD Cooperative Study–Activities of Daily Living Inventory (instrumental subset) (ADCS-iADL). Quality of life was assessed using the European Quality of Life–5 Dimensions scale, proxy version (proxy utility score and visual analog scale score), and the Quality of Life in AD scale, self-report and proxy (caregiver) versions. Group comparisons of changes from baseline to 18 months in cognitive, functional, and quality-of-life measures employed a repeated-measures model adjusted for propensity score, study, baseline cognition score (functional or quality of life), age, sex, level of education, genotype of the apolipoprotein E gene, and concurrent use of an acetylcholinesterase inhibitor or memantine. Findings At baseline, patients with mild AD dementia with and without diabetes did not significantly differ on the cognitive measures, but those without diabetes were functioning at a significantly higher level. At 18 months, compared with patients without diabetes, those with diabetes showed a numerically but statistically nonsignificantly lesser cognitive decline (least squares mean between-group differences: ADAS-Cog 14 score, 1.61 [ P = 0.21]; MMSE score, –0.40 [ P = 0.49]) and a statistically significantly lesser functional decline (least squares mean between-group difference in ADCS-iADL score, –3.07; P = 0.01). The 2 groups did not differ on declines in the quality-of-life measures. Implications The present findings suggest that diabetes may influence the rate of functional decline among patients with mild AD dementia. These results require replication in studies that address the limitations of the present post hoc exploratory analysis and that explore the potential causes of the observed differences.

The American Diabetes Association consensus statement on the treatment of type 2 diabetes mellitus (T2DM) in older patients highlights the need for treatment pattern and effectiveness data from real-world settings and populations. This retrospective cohort study assessed the relative frequency of use of four commonly prescribed antihyperglycemia treatments for T2DM and quantified their effectiveness up to 2 years post-initiation.Within a large, U.S.-based, electronic health record database, we investigated usage of insulin, sulfonylureas, glucagon-like peptide-1(GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with T2DM, focusing on those ≥65 years old, although younger patients were included for comparative purposes.Inclusion criteria were met by 77,440 patients. Mean baseline glycosylated hemoglobin (HbA1c) levels for patients ≥65 years old varied among treatments: insulin (7.7% [61 mmol/mol]; n=3,311), sulfonylureas (7.0% [53 mmol/mol]; n=5,706), GLP-1 receptor agonists (7.1% [54 mmol/mol]; n=260), and DPP-4 inhibitors (7.1% [54 mmol/mol]; n=1,096). Older patients demonstrated good glycemic control at therapy initiation and were prescribed glucose-lowering agents at lower HbA1c values compared with younger patients. A large proportion of older patients were prescribed sulfonylureas (56%) and insulin (34%) compared with GLP-1 receptor agonists (3.4%) and DPP-4 inhibitors (12%), despite the associated risk of hypoglycemia.Patients initiating insulin and sulfonylureas demonstrated more sustained glycemic control compared with GLP-1 receptor agonists and DPP-4 inhibitors. A majority of older patients with T2DM was initiated on sulfonylureas and insulin at relatively low levels of HbA1c, a practice not entirely consistent with the recommendations of published guidelines.

OBJECTIVE Traditional blood glucose–lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in β-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp–derived measures of β-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: −0.8 ± 0.1 and −0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference −4.6 kg, P < 0.0001). β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS Exenatide significantly improves β-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, β-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

Metabolic syndrome represents a cluster of risk factors commonly associated with obesity and diabetes that in turn are associated with an increased risk of cardiovascular disease. The worldwide prevalence of metabolic syndrome, obesity, and diabetes is on the rise, leading to serious public health concerns surrounding the downstream consequences in the form of premature cardiovascular disease. In this review, we examine the debate surrounding the characterization and diagnosis of metabolic syndrome and discuss potential treatment options.

Purpose The purpose of this study was to evaluate the impact of a tobacco cessation intervention using motivational interviewing on smoking cessation rates during diabetes self-management training (DSMT). Methods A randomized controlled trial was conducted with subjects recruited from an ongoing type 2 diabetes adult education program at a large diabetes center. A total of 114 subjects were randomized to intervention (n = 57; face-to-face motivational interviewing plus telephone counseling and offering of medication) or standard care (n = 57). Outcome measures included tobacco cessation rates, mean number of cigarettes smoked, A1C, weight, blood pressure, and lipids. Results Intensive intervention using motivational interviewing integrated into a standard DSMT program resulted in a trend toward greater abstinence at 3 months of follow-up in those receiving the intervention. However, this same trend was not observed at 6 months. The addition of this structured smoking cessation intervention did not negatively affect either diabetes education or other measures of diabetes management, including A1C values.

Current strategies for the treatment of type 2 diabetes target deficient insulin secretion and insulin resistance, but have not been shown to correct the progressive β-cell dysfunction characteristic of the disease. Traditionally, type 2 diabetes is treated in a stepwise manner with medical nutrition therapy, oral anti-diabetes therapies, and ultimately exogenous insulin. These therapies improve glycemic control, but are unable to prevent or delay either deterioration in glucose control or the decline of β-cell function. Despite the use of current anti-diabetes therapies, patients with type 2 diabetes are likely to experience deteriorating glycemic control and substantial weight gain. In addition to these issues, patients treated with insulin secretogogues such as sulfonylureas and exogenous insulin are subject to an increased risk of hypoglycemia. Moreover, insulin-based therapies do not fully address the complex hormonal irregularities, such as glucagon hypersecretion, that characterize type 2 diabetes. In view of the drawbacks associated with current treatment strategies, new therapies are being developed that may provide more durable glycemic control with associated reductions in body weight. These new therapies include the incretin mimetics, agents that share many of the glucoregulatory effects of the incretin hormones such as glucagon-like peptide-1 (GLP-1). Leveraging the physiological functions of incretin hormones such as GLP-1 may potentially benefit the ever growing number of patients with type 2 diabetes.

Editor’s note: This commentary was originally solicited as part of a Point-Counterpoint feature, but the author of the Counterpoint failed to provide the promised manuscript. Thiazolidinediones (TZDs), or “glitazones,” were first introduced for the treatment of type 2 diabetes in 1996, when troglitazone (Rezulin; Parke-Davis/Warner-Lambert) was approved by the Food and Drug Administration. Since the introduction of this unique class of compounds, many clinicians have embraced their use, whereas others have debated the role of insulin-sensitizing therapy for the management of type 2 diabetes. While troglitazone was withdrawn from the market in 2000 due to idiosyncratic hepatoxicity, two other glitazones, pioglitazone (Actos; Takeda Chemical Industries) and rosiglitazone (Avandia; GlaxoSmithKline), continue to be widely used by clinicians. Before the introduction of glitazones, conventional management of type 2 diabetes involved stepwise addition of medical nutrition therapy, sulfonylureas, and metformin. Despite broader use of early drug therapy, many patients do not achieve adequate blood glucose control (1). Even in those who do achieve treatment targets, a gradual deterioration in blood glucose control is often seen (2). These observations have prompted clinicians to use newer therapies, such as the glitazones, and have increased the use of early combination therapy to achieve glycemic targets Glitazones uniquely target insulin resistance—a core physiologic defect in those with type 2 diabetes—and by so doing significantly improve glucose control. Glitazones improve insulin action in muscle, adipose, and hepatic tissue by acting as agonists of peroxisome proliferator–activated receptor-γ (PPAR-γ) nuclear receptors. Activation of PPAR-γ results in a myriad of both metabolic and vascular effects by upregulating and downregulating expression of numerous genes, including genes known to regulate lipid and glucose metabolism, vascular function, thrombotic function, and the inflammatory response. Glitazones increase nonoxidative glucose disposal, increase triglyceride synthesis, and improve free fatty acid (FFA) metabolism (3). Glitazones also lower blood pressure, …

We evaluated the clinical accuracy, precision, and ease-of-use of a whole blood referenced glucose meter system that uses a 10-test disk (Ascensia Confirm Blood Glucose Monitoring System, Bayer Healthcare LLC). The meter system was tested by 100 subjects and eight health care professionals at two separate diabetes centers. Meter blood glucose test results, obtained by the subjects and health care professionals, were accurate and correlated well when compared with laboratory results. The means of the subject and healthcare professional blood glucose results were within 4.8% of the laboratory mean glucose result. When compared with laboratory results, the correlation coefficient was 0.96 for subject meter results and 0.97 for health care professional meter results. Error grid analyses demonstrated that all subject and health care professional blood glucose measurements fell within zones A and B ('no effect on clinical action' and 'altered clinical action with little or no effect on clinical outcome,' respectively). Ninety-three percent (93%) of subjects rated the meter system favorably on an 'ease-of-use' questionnaire. A majority of subjects correctly performed blood glucose self-monitoring tasks simply by reviewing the user guide. In summary, this unique meter that uses a 10-test disk was shown to be both accurate and precise, and subjects with diabetes were able to use the system properly with minimal instructions.

To construct a novel and clinically relevant means of representing self-monitored blood pressure (SMBP).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.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.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 whether clinically significant differences exist in fasting blood glucose (BG) at the forearm, palm, and thigh relative to the fingertip; to assess the impact of prandial status by comparing BG between alternative sites and the fingertip at several time intervals after carbohydrate intake; to assess the effects of moderate brief exercise on site-to-site differences in BG; to evaluate the impact of site preparation by local rubbing on alternative-site testing (AST) equivalence; and to determine levels of perceived pain and satisfaction associated with AST. RESEARCH DESIGN AND METHODS—Fasting BG was measured using the One Touch Ultra (LifeScan, Milpitas, CA) at the fingertip, palm, thigh, and each forearm (with local rubbing) in 86 patients with type 2 diabetes. A 40-g carbohydrate meal was consumed and BG was again measured from each site at 60, 90, and 120 min postmeal, with an additional forearm test at 90 min without local rubbing. Patients then exercised for 15 min with repeat BG at each site. Differences in BG between sites were assessed using repeated-measures ANOVA and regression analyses. RESULTS—Significant differences in BG at alternative sites were found 60 min postmeal (P = 0.0003) and postexercise (P = 0.037). Specifically, clinically significant differences (expressed as percent difference from the fingertip) at 60 min include −8.8 ± 10.8% at the forearm and −13.7 ± 10.7% at the thigh, and postexercise +19.1 ± 19.1% at the forearm and +15.6 ± 22.6% at the thigh. However, no significant differences were observed between sites in either the fasting state or at 90 and 120 min postmeal. The dynamic results suggest a time lag in equilibration of forearm and thigh BG during periods of rapid glucose change. Palm and fingertip BG test results were similar at all time points. CONCLUSIONS—AST results are consistent with fingertip BG results in both the fasting state and 2 h postmeal; no benefit from site preparation by local rubbing was noted. However, testing at sites other than the hand cannot be recommended 1 h postmeal or immediately after exercise. AST is equivalent and appropriate for use at testing times commonly used in clinical practice.

We report a case of severe hypoglycemia occurring in a 35-yr-old woman, 6 yr after pancreas transplantation for type 1 diabetes mellitus. Extensive preoperative and intraoperative exploration failed to disclose the presence of a focal adenomatous lesion. Partial allograft pancreatectomy was performed initially, but it failed to control the hypoglycemic symptoms, leading to complete removal of the pancreas allograft. Histopathological examination of the resected pancreas allograft showed the presence of nesidioblastosis, characterized by foci of islet cells budding off ducts, accompanied by an increase in the number of islets, numerous small intralobular islet cell aggregates, and nesidiodysplasia (large, hyperchromatic islet cell nuclei). Islet neogenesis-associated protein-positive islets and ducts were seen by immunofluorescence. Insulin-positive islets ranged from very small to large, with isolated insulin-positive cells diffusely scattered, consistent with islet neogenesis. Very little glucagon staining was identified. Reported cases of adult nesidioblastosis are reviewed. The significance of nesidioblastosis in the context of pancreas transplantation and possible mechanisms of posttransplant hypoglycemia are discussed.

OBJECTIVES— The current study was conducted to compare the effectiveness of delivering diabetes education in either a group or individual setting using a consistent, evidence-based curriculum. RESEARCH DESIGN AND METHODS— A total of 170 subjects with type 2 diabetes were randomly assigned to either group (n = 87) or individual (n = 83) educational settings. Subjects received education in four sequential sessions delivered at consistent time intervals over a 6-month period. Outcomes included changes in knowledge, self-management behaviors, weight, BMI, HbA1c, health-related quality of life, patient attitudes, and medication regimen. Changes were assessed at baseline and after the 2-week, 3-month, and 6-month education sessions. RESULTS— Both educational settings had similar improvements in knowledge, BMI, health-related quality of life, attitudes, and all other measured indicators. HbA1c decreased from 8.5 ± 1.8% at baseline to 6.5 ± 0.8% at 6 months (P < 0.01) in the study population as a whole. Subjects assigned to the individual setting had a 1.7 ± 1.9% reduction in HbA1c (P < 0.01), whereas subjects assigned to the group setting had a 2.5 ± 1.8% reduction in HbA1c (P < 0.01). The difference in HbA1c improvement was marginally greater in subjects assigned to group education versus individualized education (P = 0.05). CONCLUSIONS— This study demonstrates that diabetes education delivered in a group setting, when compared with an individual setting, was equally effective at providing equivalent or slightly greater improvements in glycemic control. Group diabetes education was similarly effective in delivering key educational components and may allow for more efficient and cost-effective methods in the delivery of diabetes education programs.

OBJECTIVE The standard dynamic test used to diagnose hypopituitarism is the insulin tolerance test (ITT), in which insulin-induced secretion of ACTH, GH and cortisol is measured. However, because of differences in insulin sensitivity some patients fail achieve sufficient hypoglycaemia to assess pituitary function and colleagues experience severe hypoglycaemia and are at risk for cardiac dysrhythmia, seizure or coma. This risk may be particularly pertinent in the evaluation of older adults. We hypothesized that the hypoglycaemic clamp may be useful in assessing pituitary function in some patients. PATIENTS AND MEASUREMENTS Twenty-one normal subjects (14 old [50–76 years] and 7 young [18–36 years]) and 7 hypopituitary subjects were studied. A clamp study was performed in which insulin infusion was given at 2 mU/kg/min and increased to 4 mU/kg/min if the target glucose concentration was not reached after 40 min. Dextrose was infused as needed to clamp the plasma glucose concentration at 2.2 mmol/l for 30 min. On a separate day, 7 young controls also underwent an ITT in which 0.15 U/kg insulin was administered as a bolus intravenous injection at time 0. In both studies, baseline values were taken at - 10, - 5 and 0 min. Samples were then collected every 5 min for plasma glucose and every 10 min for insulin, ACTH, cortisol and GH. RESULTS ACTH and GH secretion during each test were similar in younger controls (P = NS) but cortisol secretion was lower during ITT (P

Impaired epinephrine secretion and symptom unawareness are characteristic of severe hypoglycemia in individuals with long-standing type I diabetes. Recently, the avoidance of clinical hypoglycemia has been reported to improve epinephrine and symptom responses to hypoglycemia in type I patients. However, the extent to which these defects can be restored in individuals with long-standing type I diabetes and autonomic neuropathy has not been assessed, nor has it been determined whether pancreas transplantation, which not only obviates hypoglycemia but also prevents hyperglycemia, results in the complete recovery of either epinephrine response or symptom awareness during insulin-induced hypoglycemia. We performed stepped hypoglycemic clamp studies in successful pancreas transplantation recipients to assess epinephrine and other counterregulatory hormone responses during hypoglycemia and to determine the degree to which hypoglycemic symptom recognition could be restored. Thirteen pancreas transplant recipients and matched control subjects were studied utilizing stepped hypoglycemic clamp protocol to achieve target glucose levels of 3.9, 3.3, 2.8, and 2.2 mmol/l (70, 60, 50, and 40 mg/dl, respectively). Plasma epinephrine response was significantly greater in healthy control subjects and pancreas transplant patients compared with type I subjects at the glucose plateaus of 3.9, 3.3, and 2.8 mmol/l. However, epinephrine response in pancreas transplant recipients was significantly less than that seen in either healthy control subjects or nondiabetic kidney transplant recipients at each of these glucose plateaus. The magnitude of the epinephrine response in pancreas transplant type I patients did not correlate with either the duration of diabetes, the duration of transplantation, or the measures of autonomic nerve function. Hypoglycemic symptom recognition was significantly greater in pancreas transplant subjects than type I patients and did not differ between pancreas transplant and control groups. No improvement in norepinephrine response was observed after pancreas transplantation, while glucagon responses to hypoglycemia were normalized in pancreas transplant patients. In conclusion, these studies uniquely demonstrate that successful pancreas transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with long-standing diabetes and established autonomic neuropathy. No correlation was observed between the severity of autonomic neuropathy or the duration of diabetes and the recovery of either the epinephrine or symptom responses to hypoglycemia.

The optimal site for pancreatic islet cell transplantation is presently unclear, although the liver has been the most commonly used. However, glucagon secretion from islets that have been autotransplanted in liver has been reported to be unresponsive to hypoglycemia yet responsive to arginine. To determine whether this selective glucagon secretory defect is related to the intrahepatic site of islet implantation or to the process of transplantation per se, we studied counterregulatory responses to hypoglycemia in dogs with pancreatic islet autotransplantation in the hepatic parenchyma (the intrahepatic [IH] group, n = 9) or the peritoneal cavity (the intraperitoneal [IP] group, n = 9), following total pancreatectomy, and compared them with the responses in normal controls (n = 10). Dogs were subjected to a hypoglycemic hyperinsulinemic (5 mU · kg−1 min−1) clamp for 90 min under general anesthesia. Arterial glucose concentrations were clamped at 2.7 mmol/l for the final 45 min of the clamp. Immediately following the clamp, glucagon responses to IV arginine (5 g) were also assessed. During hypoglycemia, glucagon responses in the IH group (maximal incremental glucagon = 33 ± 21 ng/l; glucagon area under curve [AUC] = 713 ± 1,022 ng · 1−1 · min−1) were significantly lower than either the IP (maximal incremental glucagon = 92 ± 32 ng/l; glucagon AUC = 4,090 ± 1,600 ng · 1−1 · min−1) or control (maximal incremental glucagon = 154 ± 71 ng/l; glucagon AUC = 6,943 ± 2,842 ng · 1−1 · min−1) group (IH vs. IP group, P < 0.05; control vs. IH group, P < 0.01). Glucagon responses in the IP group did not differ significantly from the control group. Epinephrine responses to hypoglycemia were similar in all groups, whereas neither of the transplanted groups (IH and IP) had pancreatic polypeptide responses. There was a prompt rise in plasma glucagon after intravenous arginine in all groups. These data indicate that glucagon unresponsiveness to hypoglycemia is specific to intrahepatically transplanted islets, rendering the liver a disadvantageous site for optimal α-cell function.

Transplantation of pancreatic islets, rather than whole pancreas, has been introduced as a treatment for diabetes mellitus. We studied five patients ranging in age from 12 to 37 years who had severe chronic pancreatitis for which they underwent total pancreatectomy followed by isolation and hepatic transplantation of their own islets.All patients had remained insulin-independent for 1 to 7 1/2 years after transplantation. The numbers of islets transplanted ranged from 110,000 to 412,000. Islet function was assessed by measuring the plasma insulin responses to intravenous glucose and arginine and the plasma glucagon responses to hypoglycemia and arginine. In one patient, islet function was studied during catheterization of the hepatic vein, portal vein, and splenic artery and by analysis of a liver-biopsy specimen.After transplantation, the mean (+/- SD) fasting plasma glucose concentration was 122 +/- 47 mg per deciliter (6.8 +/- 2.6 mmol per liter) and the hemoglobin A1c concentration was 6.0 +/- 0.8 percent in the five patients. The values were most abnormal--214 mg per deciliter (11.9 mmol per liter) and 7.3 percent, respectively--in the patient who received only 110,000 islets. The acute plasma insulin responses to glucose and to arginine in the five patients were 23 +/- 13 and 26 +/- 10 microU per milliliter (168 +/- 94 and 184 +/- 70 pmol per liter), respectively, as compared with 58 +/- 6 and 37 +/- 8 microU per milliliter (416 +/- 44 and 267 +/- 61 pmol per liter) in the normal subjects. The peak plasma glucagon responses to insulin and arginine were 21 +/- 4 and 65 +/- 36 pg per milliliter, respectively, as compared with 125 +/- 28 and 156 +/- 99 pg per milliliter in the normal subjects. All five patients had plasma epinephrine but not pancreatic polypeptide responses to hypoglycemia. The results of the hepatic-vein catheterization in one patient indicated that the transplanted islets released insulin and glucagon in response to arginine. Immunoperoxidase staining of this patient's liver-biopsy specimen showed that the islets contained insulin, glucagon, and somatostatin but not pancreatic polypeptide.Intrahepatic transplantation of as few as 265,000 islets can result in the release of insulin and glucagon at appropriate times and in prolonged periods of insulin independence.

Incretin-based therapies address the progressive nature of type 2 diabetes mellitus, not only by addressing glucose control but also with weight-neutral (i.e., dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin) and weight-reducing effects (i.e., glucagonlike peptide-1 [GLP-1] receptor agonists exenatide and liraglutide). Preclinical data suggest that incretin-based therapies may also preserve beta-cell function, holding promise of a truly disease-modifying therapy. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of these agents in routine clinical practice. We propose a systematic approach to treatment, addressing (1) patient selection, (2) optimal treatment combinations, and (3) timing and guidance for both initiation and intensification of therapy. The GLP-1 receptor agonists, for example, could be particularly beneficial in patients whose weight significantly increases cardiovascular risk. Early use of these agents may be effective in preventing diabetes in those at risk, or in halting or retarding disease progression in patients with frank diabetes. Additional clinical investigation will be required to test such hypotheses. Given the ever-increasing incidence of diabetes worldwide, the link between obesity and the development of type 2 diabetes, and the need for more effective, weight-focused, convenient and sustainable treatments, the data from such studies will be invaluable to further clarify the role of the incretins in the management of patients with type 2 diabetes.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

Summary Background Exenatide is an incretin mimetic that shares glucoregulatory properties with glucagon-like peptide 1 (GLP-1), and improves glycaemic control, with progressive bodyweight reductions, when administered twice a day in patients with type 2 diabetes. We compared the efficacy of a once-weekly formulation of exenatide to that of a twice daily dose. Methods A 30-week, randomised, non-inferiority study compared a long-acting release formulation of exenatide 2 mg administered once weekly to 10 μg exenatide administered twice a day, in 295 patients with type 2 diabetes (haemoglobin A 1c [HbA 1c ] 8·3% [SD 1·0], mean fasting plasma glucose 9 [SD 2] mmol/L, weight 102 [SD 20] kg, diabetes duration 6·7 [SD 5·0] years). The patients were naive to drug therapy, or on one or more oral antidiabetic agents. The primary endpoint was the change in HbA 1c at 30 weeks. This study is registered with ClinicalTrials.gov, number NCT00308139. Findings At 30 weeks, the patients given exenatide once a week had significantly greater changes in HbA 1c than those given exenatide twice a day (−1·9 [SE 0·1%] vs −1·5 [0·1%], 95% CI −0·54% to −0·12%; p=0·0023). A significantly greater proportion of patients receiving treatment once a week versus twice a day achieved target HbA 1c levels of 7·0% or less (77% vs 61% of evaluable patients, p=0·0039). Interpretation Exenatide once weekly resulted in significantly greater improvements in glycaemic control than exenatide given twice a day, with no increased risk of hypoglycaemia and similar reductions in bodyweight. Funding Amylin Pharmaceuticals Inc and Eli Lilly and Company.

Pancreatic tissue obtained by hemipancreatectomy from healthy living related donors has been transplanted into recipients with Type I diabetes mellitus. To determine the metabolic consequences of this procedure for the donors, we carried out oral glucose-tolerance testing and 24-hour monitoring of serum glucose levels and urinary C-peptide excretion as a measure of insulin secretion in 28 donors, both before and one year after hemipancreatectomy. The mean fasting serum glucose level was significantly higher one year after the procedure (mean +/- SD, 5.4 +/- 0.9 vs. 4.9 +/- 0.5 mmol per liter; P less than 0.003), as was the serum glucose value two hours after the administration of glucose (8.7 +/- 2.9 vs. 6.5 +/- 1.0 mmol per liter; P less than 0.001). The fasting serum insulin level was significantly lower one year after hemipancreatectomy (33.0 +/- 21.6 vs. 38.4 +/- 21.6 pmol per liter; P less than 0.05), as was the area under the insulin curves during the oral glucose-tolerance test (52,554 +/- 22,320 vs. 76,230 +/- 33,354 pmol per liter per minute; P less than 0.04). The mean 24-hour serum glucose-profile value was higher at one year, and the 24-hour urinary C-peptide excretion was lower in the 17 donors who underwent these studies. Seven of the 28 donors had abnormal glucose tolerance one year after hemipancreatectomy; however, insulin secretion in these 7 donors was indistinguishable from that in the 21 donors who had normal glucose tolerance. All 28 donors had fasting serum glucose concentrations lower than 7.8 mmol per liter, and their mean 24-hour plasma glucose levels remained within the normal range. We conclude that in healthy donors hemipancreatectomy results in a deterioration of insulin secretion and glucose tolerance, as measured one year later. Further study is required to ascertain whether the development of clinical diabetes mellitus is a risk inherent in hemipancreatectomy.

Although depression is often associated with poor glycemic control in patients with type 2 diabetes mellitus (T2DM), this observation has been inconsistent. This exploratory, post hoc analysis investigated associations between depression parameters and glycemic control using data from a 24-month, prospective, observational, non-interventional study evaluating glycemic response following insulin initiation for T2DM.We analyzed data from a 24-month, prospective, observational study that evaluated glycemic response in patients with T2DM who initiated insulin therapy (N = 985) in 5 European countries. Secondary measures included patient-reported diagnosis of depression at baseline, severity of depressed/anxious mood (EuroQol (EQ)-5D item) and diabetes-related distress (Psychological Distress domain of the Diabetes Health Profile, DHP-18). The latter two measures were assessed at baseline and 5 time points throughout the study. Glycemic control was measured by glycated hemoglobin (HbA1c) at these same time points. Analyses employed t tests to assess the unadjusted baseline difference in HbA1c between patients with and without the respective depression parameter. The potential effect of demographic and clinical confounding variables was controlled through a linear model structure. Patient HbA1c levels were analyzed by presence/absence of a history of diagnosed depression, depressed mood, and diabetes-related distress.Patients with higher depression parameters or distress at baseline had significantly higher rates of microvascular complications at baseline. Patients with a history of diagnosed depression or high diabetes-related distress had higher HbA1c than patients without. HbA1c of patients with or without depressed mood was not significantly different at baseline. The proportion of patients with depressed mood declined after insulin initiation, whereas the proportion of patients with high diabetes-related distress did not significantly change. HbA1c improved following insulin initiation, regardless of presence/absence of studied depression/distress parameters at baseline.History of diagnosed depression, diabetes-related distress, and depressed mood were associated with a higher rate of microvascular complications. Diagnosed depression and diabetes-related distress also showed higher HbA1c at baseline when insulin was initiated. Insulin therapy improved glycemic control, while preexisting depressed mood declined and diabetes-related distress remained unchanged.

We sought to evaluate the effects of muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor (PPAR) activator within the new glitazar class, on hyperglycemia and lipid abnormalities.A double-blind, randomized, controlled trial was performed in 1,159 patients with type 2 diabetes inadequately controlled with metformin. Patients received once-daily doses of either 5 mg muraglitazar or 30 mg pioglitazone for a total of 24 weeks in addition to open-label metformin. Patients were continued in a double-blind fashion for an additional 26 weeks.Analyses were conducted at week 24 for HbA1c (A1C) and at week 12 for lipid parameters. Mean A1C at baseline was 8.12 and 8.13% in muraglitazar and pioglitazone groups, respectively. At week 24, muraglitazar reduced mean A1C to 6.98% (-1.14% from baseline), and pioglitazone reduced mean A1C to 7.28% (-0.85% from baseline; P0.0001, muraglitazar vs. pioglitazone). At week 12, muraglitazar and pioglitazone reduced mean plasma triglyceride (-28 vs. -14%), apolipoprotein B (-12 vs. -6%), and non-HDL cholesterol (-6 vs. -1%) and increased HDL cholesterol (19 vs. 14%), respectively (P0.0001 vs. pioglitazone for all comparisons). At week 24, weight gain (1.4 and 0.6 kg, respectively) and edema (9.2 and 7.2%, respectively) were observed in the muraglitazar and pioglitazone groups; at week 50, weight gain and edema were 2.5 and 1.5 kg, respectively, and 11.8 and 8.9%, respectively. At week 50, heart failure was reported in seven patients (five with muraglitazar and two with pioglitazone), and seven deaths occurred: three from sudden death, two from cerebrovascular accident, and one from pancreatic cancer in the muraglitazar group and one from perforated duodenal ulcer in the pioglitazone group.We found that 5 mg muraglitazar resulted in greater improvements in A1C and lipid parameters than a submaximal dose of 30 mg pioglitazone when added to metformin. Weight gain and edema were more common when muraglitazar was compared with a submaximal dose of pioglitazone.

Diabetic dyslipidemia is characterized by high triglyceride levels; low high-density lipoprotein cholesterol levels; small, dense low-density lipoprotein particles; and high free fatty acid levels. Niacin reduces concentrations of triglyceride-rich and small low-density lipoprotein particles while increasing high-density lipoprotein cholesterol levels. It also lowers levels of free fatty acids and lipoprotein(a). However, the use of niacin in patients with diabetes has been discouraged because high doses can worsen glycemic control. We evaluated the efficacy and safety of once-daily extended-release (ER) niacin in patients with diabetic dyslipidemia.During a 16-week, double-blind, placebo-controlled trial, 148 patients were randomized to placebo (n = 49) or 1000 (n = 45) or 1500 mg/d (n = 52) of ER niacin. Sixty-nine patients (47%) were also receiving concomitant therapy with statins.Dose-dependent increases in high-density lipoprotein cholesterol levels (+19% to +24% [P.05] vs placebo for both niacin dosages) and reductions in triglyceride levels (-13% to -28% [P.05] vs placebo for the 1500-mg ER niacin) were observed. Baseline and week 16 values for glycosylated hemoglobin levels were 7.13% and 7.11%, respectively, in the placebo group; 7.28% and 7.35%, respectively, in the 1000-mg ER niacin group (P=.16 vs placebo); and 7.2% and 7.5%, respectively, in the 1500-mg ER niacin group (P=.048 vs placebo). Four patients discontinued participation because of inadequate glucose control. Rates of adverse event rates other than flushing were similar for the niacin and placebo groups. Four patients discontinued participation owing to flushing (including 1 receiving placebo). No hepatotoxic effects or myopathy were observed.Low doses of ER niacin (1000 or 1500 mg/d) are a treatment option for dyslipidemia in patients with type 2 diabetes.

The current study was conducted to compare the effectiveness of delivering diabetes education in either a group or individual setting using a consistent, evidence-based curriculum.A total of 170 subjects with type 2 diabetes were randomly assigned to either group (n = 87) or individual (n = 83) educational settings. Subjects received education in four sequential sessions delivered at consistent time intervals over a 6-month period. Outcomes included changes in knowledge, self-management behaviors, weight, BMI, HbA(1c), health-related quality of life, patient attitudes, and medication regimen. Changes were assessed at baseline and after the 2-week, 3-month, and 6-month education sessions.Both educational settings had similar improvements in knowledge, BMI, health-related quality of life, attitudes, and all other measured indicators. HbA(1c) decreased from 8.5 +/- 1.8% at baseline to 6.5 +/- 0.8% at 6 months (P0.01) in the study population as a whole. Subjects assigned to the individual setting had a 1.7 +/- 1.9% reduction in HbA(1c) (P0.01), whereas subjects assigned to the group setting had a 2.5 +/- 1.8% reduction in HbA(1c) (P0.01). The difference in HbA(1c) improvement was marginally greater in subjects assigned to group education versus individualized education (P = 0.05).This study demonstrates that diabetes education delivered in a group setting, when compared with an individual setting, was equally effective at providing equivalent or slightly greater improvements in glycemic control. Group diabetes education was similarly effective in delivering key educational components and may allow for more efficient and cost-effective methods in the delivery of diabetes education programs.

Source Citation Goudswaard AN, Furlong NJ, Rutten GE, Stolk RP, Valk GD. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus....