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AIMS: To test whether a long-acting GLP-1 receptor agonist would improve glucose control in patients with type 1 diabetes (T1D) and to determine whether the presence of residual beta cell function would affect the response. In addition, we sought to determine whether the drug would affect beta cell function. METHODS: We performed a randomized placebo-controlled trial of exenatide extended release (ER) in participants with T1D with and without detectable levels of C-peptide. Seventy-nine participants were randomized to exenatide ER 2 mcg weekly, or placebo, stratified by the presence or absence of detectable C-peptide levels. The primary outcome was the difference in glycated haemoglobin (HbA1c) levels at 24 weeks. Participants were followed for another 6 months off study drug. RESULTS: At week 24, the time of the primary outcome, the least squares (LS) mean HbA1c level was 7.76% (95% confidence interval [CI] 7.42, 8.10) in the exenatide ER group versus 8.0% (95% CI 7.64, 8.35) in the placebo group (P = 0.08). At week 12 the LS mean HbA1c levels were 7.71% (95% CI 7.37, 8.05) in the exenatide ER group versus 8.05% (95% CI 7.7, 8.4) in the placebo group (P = 0.01). The improvement at week 12 was driven mainly by those with detectable levels of C-peptide. Those treated with exenatide ER lost weight at 12 and 24 weeks compared to those treated with placebo (P

BackgroundType 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.MethodsWe conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.ResultsA total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.ConclusionsTeplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

Context Decreased first-phase insulin response (FPIR) during intravenous glucose tolerance testing (IVGTT) is an early indicator of β-cell dysfunction and predictor of type 1 diabetes (T1D). Objective Assess whether oral glucose tolerance test (OGTT) measures could serve as FPIR alternatives in their ability to predict T1D in autoantibody positive (Aab+) subjects. Design OGTT and IVGTT were performed within 30 days of each other. Eleven OGTT variables were evaluated for (1) correlation with FPIR and (2) T1D prediction. Setting Type 1 Diabetes TrialNet “Oral Insulin for Prevention of Diabetes in Relatives at Risk for T1D” (TN-07) and Diabetes Prevention Trial-Type 1 Diabetes (DPT-1) studies clinical sites. Patients TN-07 (n = 292; age 9.4 ± 6.1 years) and DPT-1 (n = 194; age 15.1 ± 10.0 years) Aab + relatives of T1D individuals. Main outcome measures (1) Correlation coefficients of OGTT measures with FPIR and (2) T1D prediction at 2 years using area under receiver operating characteristic (ROCAUC) curves. Results Index60 showed the strongest correlation in DPT-1 (r = -0.562) but was weaker in TN-07 (r = -0.378). C-peptide index consistently showed good correlation with FPIR across studies (TN-07, r = 0.583; DPT-1, r = 0.544; P Conclusions C-peptide index was the strongest measure to correlate with FPIR in both studies. Index60 and C-peptide index had the highest predictive accuracy for T1D and were comparable. OGTTs could be considered instead of IVGTTs for subject stratification in T1D prevention trials.

OBJECTIVE Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody-positive individuals to assess 1) characteristic GRC changes during progression to type 1 diabetes and 2) GRC changes in relation to β-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes. RESEARCH DESIGN AND METHODS Among antibody-positive individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n = 298) to type 1 diabetes and nonprogressors (n = 2,216). GRC changes from last OGTT before diagnosis to diagnostic OGTTs were studied in progressors. RESULTS GRCs changed more frequently from biphasic (two peaks) to monophasic (one peak) GRCs between first and last OGTTs in progressors than in nonprogressors (75.4% vs. 51.0%, respectively; P < 0.001). In contrast, GRCs of progressors changed less frequently from monophasic to biphasic than those of nonprogressors (12.6% vs. 30.6%; P < 0.001). Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30–0 min) C-peptide response decreased in progressors with GRCs changing from biphasic to monophasic between first and last OGTTs (P < 0.001) and from monophasic to monotonic between last and diagnostic OGTTs (P < 0.001). Conversely, the early C-peptide response increased among nonprogressors with GRCs changing from monophasic to biphasic (P < 0.001). Changes in GRCs were related to changes in GCRCs. CONCLUSIONS Characteristic GRC changes, biphasic to monophasic to monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing β-cell function.

OBJECTIVE A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration RESEARCH DESIGN AND METHODS A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025. RESULTS The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively. CONCLUSIONS Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.

Individuals with a biphasic (BP; two peaks) GRC during a 2-hour oral glucose tolerance test (OGTT) are at lower risk of T1D than those with monophasic (MP; one peak) and monotonic (MT; continuous increase) GRCs. We thus performed a longitudinal analysis to examine whether: 1) the different GRC risks are indicative of changes in GRC shapes during the progression to T1D, and 2) changes in GRCs are related to a deterioration in β-cell function. Changes in shapes of GRCs were compared between progressors [n=360; mean age 13.8±10.9 years; 47.3% male] and non-progressors [n=2404; mean age 18.1±13.1 years; 52.1% male] from first OGTTs to last OGTTs (before diagnosis for progressors). Median intervals from first to last OGTTs for progressors and non-progressors were 1.6 (0.9, 3.0) and 2.1 (1.0, 4.4) years, respectively. Logistic regression was used with adjustments for baseline age, sex, BMIZ and the interval between OGTTs. Progressor GRCs changed significantly more frequently than non-progressor GRCs from BP to MP [70.7% (29/41) vs. 46.3% (271/585); adjusted OR 3.00 (1.42-6.33); p=0.004)], and from MP to MT [12.4% (31/251) vs. 1.7% (19/1119); adjusted OR 8.85 (4.60-17.00); p In conclusion, GRC risk differences for T1D result from characteristic changes in GRCs during progression. A substantial proportion of progressors to T1D evolve to MT GRCs at diagnosis. Reductions in the early C-peptide response correspond to changes in GRCs from BP to MP and from MP to MT, which suggests that the changes in GRCs reflect a pathological decline in β-cell function. Disclosure H.M. Ismail: None. P. Xu: None. D.J. Becker: None. I. Libman: Consultant; Self; Novo Nordisk A/S. J.B. Marks: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Abvance. Consultant; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim GmbH. Advisory Panel; Self; Dance Biopharm. Consultant; Self; Diavacs, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Ideal Life Inc., ImmunoMolecular Therapeutics, Intrexon, Merck & Co., Inc.. Advisory Panel; Self; Orgenesis Inc.. Consultant; Self; Sanofi, Servier, VTV Therapeutics, Valeritas, Inc., Viacyte, Inc.. Board Member; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc.. Board Member; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. Board Member; Self; Moerae Matrix. Stock/Shareholder; Self; Moerae Matrix, Dance Biopharm, Ideal Life Inc., Intrexon, VasoPrep Surgical. J.P. Palmer: None. J. Sosenko: None.

High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction.

BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported that the number of circulating neutrophils is reduced in patients with T1D and in presymptomatic at-risk subjects. The aim of the present work was to identify possible changes in circulating and pancreas-residing neutrophils throughout the disease course to better elucidate neutrophil involvement in human T1D. METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinct studies performed by TrialNet, were analyzed with comprehensive statistical approaches to determine whether the number of circulating neutrophils correlates with pancreas function. To obtain a broad analysis of pancreas-infiltrating neutrophils throughout all disease stages, pancreas sections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) were analyzed by immunohistochemistry and immunofluorescence. Finally, circulating neutrophils were purified from unrelated nondiabetic subjects and donors at various T1D stages and their transcriptomic signature was determined by RNA sequencing. RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowest peripheral neutrophil numbers. Neutrophils infiltrate the pancreas prior to the onset of symptoms and they continue to do so as the disease progresses. Of interest, a fraction of these pancreas-infiltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specific pathogenic role. Whole-transcriptome analysis of purified blood neutrophils revealed a unique molecular signature that is distinguished by an overabundance of IFN-associated genes; despite being healthy, said signature is already present in T1D-autoantibody-negative at-risk subjects. CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both in the circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying that targeting neutrophils might represent a previously unrecognized therapeutic modality. FUNDING. Juvenile Diabetes Research Foundation (JDRF), NIH, Diabetes UK.

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6–36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome—baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years—showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168–0.268) and 0.141 nmol/L (95% CI 0.071–0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months’ delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.

OBJECTIVE We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Eighty-seven subjects (aged 8–40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome—baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year—showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months. RESULTS The rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA1c were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (P = 0.03). Odds ratio for loss of C-peptide to CONCLUSIONS Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.

We aimed to examine: (1) whether specific glucose-response curve shapes during OGTTs are predictive of type 1 diabetes development; and (2) the extent to which the glucose-response curve is influenced by insulin secretion. Autoantibody-positive relatives of people with type 1 diabetes whose baseline OGTT met the definition of a monophasic or biphasic glucose-response curve were followed for the development of type 1 diabetes (n = 2627). A monophasic curve was defined as an increase in OGTT glucose between 30 and 90 min followed by a decline of ≥ 0.25 mmol/l between 90 and 120 min. A biphasic response curve was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 0.25 mmol/l. Associations of type 1 diabetes risk with glucose curve shapes were examined using cumulative incidence curve comparisons and proportional hazards regression. C-peptide responses were compared with and without adjustments for potential confounders. The majority of participants had a monophasic curve at baseline (n = 1732 [66%] vs n = 895 [34%]). The biphasic group had a lower cumulative incidence of type 1 diabetes (p

The goal of the VA Diabetes Trial (VADT) was to determine the effect of intensive glucose control on macrovascular events in subjects with difficult-to-control diabetes. No significant benefit was found. This report examines predictors of the effect of intensive therapy on the primary outcome in this population.This trial included 1791 subjects. Baseline cardiovascular risk factors were collected by interview and the VA record. The analyses were done by intention to treat.Univariate analysis at baseline of predictors of a primary cardiovascular (CV) event included a prior CV event, age, insulin use at baseline, and duration of diagnosed diabetes (all P.0001). Multivariable modeling revealed a U-shaped relationship between duration of diabetes and treatment. Modeled estimates for the hazard ratios (HRs) for treatment show that subjects with a short duration (3 years or less) of diagnosed diabetes have a nonsignificant increase in risk (HR1.0) after which the HR is below 1.0. From 7 to 15 years' duration at entry, subjects have HRs favoring intensive treatment. Thereafter the HR approaches 1.0 and over-21-years' duration approaches 2.0. Duration over 21 years resulted in a HR of 1.977 (CI 1.77-3.320, P.01). Baseline c-peptide levels progressively declined up to 15 years and were stable subsequently.In difficult-to-control older subjects with type 2 DM, duration of diabetes altered the response to intensive glucose control. Intensive therapy may reduce CV events in subjects with a duration of 15 years or less and may increase risks in those with longer duration.

BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte–mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)

NBI-6024 is an altered peptide ligand (APL) corresponding to the 9–23 amino acid region of the insulin B chain (B(9−23)), an epitope recognized by inflammatory interferon-γ-producing T helper (Th)1 lymphocytes in type 1 diabetic patients. Immunomodulatory effects of NBI-6024 administration in recent-onset diabetic patients in a phase I clinical trial (NBI-6024-0003) were measured in peripheral blood mononuclear cells using the enzyme-linked immunosorbent spot assay. Analysis of the mean magnitude of cytokine responses to B(9−23) and NBI-6024 for each cohort showed significant increases in interleukin-5 responses (a Th2 regulatory phenotype) in cohorts that received APL relative to those receiving placebo. A responder analysis showed that Th1 responses to B(9−23) and NBI-6024 were observed almost exclusively in the placebo-treated diabetic population but not in nondiabetic control subjects and that APL administration (five biweekly subcutaneous injections) significantly and dose-dependently reduced the percentage of patients with these Th1 responses. The results of this phase I clinical study strongly suggest that NBI-6024 treatment shifted the Th1 pathogenic responses in recent-onset type 1 diabetic patients to a protective Th2 regulatory phenotype. The significance of these findings on the clinical outcome of disease is currently under investigation in a phase II multidose study.

In Brief This article offers highlights from the 2003 annual meeting of the North American Association for the Study of Obesity, which was co-sponsored by the American Diabetes Association. Topics include recent research into various diets for weight loss, the relationship between obesity and polycystic ovarian syndrome, and future treatments of obesity.

OBJECTIVE—Compare the efficacy, safety, and patient satisfaction of continuous subcutaneous insulin infusion (CSII) therapy with multiple daily injection (MDI) therapy for patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 132 CSII-naive type 2 diabetic patients were randomly assigned (1:1) to CSII (using insulin aspart) or MDI therapy (bolus insulin aspart and basal NPH insulin) in a multicenter, open-label, randomized, parallel-group, 24-week study. Efficacy was assessed with HbA1c and eight-point blood glucose (BG) profiles. Treatment satisfaction was determined with a self-administered questionnaire. Safety assessments included adverse events, hypoglycemic episodes, laboratory values, and physical examination findings. RESULTS—HbA1c values decreased similarly for both groups from baseline (8.2 ± 1.37% for CSII, 8.0 ± 1.08% for MDI) to end of study (7.6 ± 1.22% for CSII, 7.5 ± 1.22% for MDI). The CSII group showed a trend toward lower eight-point BG values at most time points (only significant 90 min after breakfast; 167 ± 48 vs. 192 ± 65 mg/dl for CSII and MDI, respectively; P = 0.019). A total of 93% of CSII-treated subjects preferred the pump to their previous injectable insulin regimen for reasons of convenience, flexibility, ease of use, and overall preference. Safety assessments were comparable for both treatment groups. CONCLUSIONS—Insulin aspart in CSII therapy provided efficacy and safety comparable to MDI therapy for type 2 diabetes. Patients with type 2 diabetes can be trained as outpatients to use CSII and prefer CSII to injections, indicating that pump therapy should be considered when initiating intensive insulin therapy for type 2 diabetes.

It is unknown whether insulin therapy can delay or prevent diabetes in nondiabetic relatives of patients with diabetes.In a randomized, controlled, nonblinded clinical trial, we screened 84,228 first-degree and second-degree relatives of patients with diabetes for islet-cell antibodies; 3152 tested positive; 2103 of the 3152 underwent genetic, immunologic, and metabolic staging to quantify their risk; 372 of the 2103 had a projected five-year risk of more than 50 percent; 339 of the 372 (median age, 11.2 years) were randomly assigned to undergo either close observation or an intervention that consisted of low-dose subcutaneous ultralente insulin, administered twice daily for a total dose of 0.25 unit per kilogram of body weight per day, plus annual four-day continuous intravenous infusions of insulin. Oral glucose-tolerance tests were performed every six months. Median follow-up was 3.7 years. The primary end point was a diagnosis of diabetes.Diabetes was diagnosed in 69 subjects in the intervention group and 70 subjects in the observation group. The annualized rate of progression to diabetes was 15.1 percent in the intervention group and 14.6 percent in the observation group. The cumulative incidence of diabetes was similar in the two groups (relative risk in the intervention group as compared with the observation group, 0.96). Most subjects in whom diabetes developed were asymptomatic. Progression to diabetes occurred at a faster rate among subjects with abnormal base-line glucose tolerance (22 percent per year) than among those with normal base-line glucose tolerance (10 percent per year, P0.001). There were no episodes of severe hypoglycemia. The incidence of chemical hypoglycemia, assessed without ascertainment bias, was similar in the two groups.In persons at high risk for diabetes, insulin at the dosage used in this study does not delay or prevent type 1 diabetes.

OBJECTIVE Blood pressure (BP) control for renal protection is essential for patients with type 2 diabetes. Our objective in this analysis of Veterans Affairs Diabetes Trial (VADT) data was to learn whether on-study systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) affected renal outcomes measured as albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). RESEARCH DESIGN AND METHODS The VADT was a prospective, randomized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events. In this post hoc study, time-varying covariate survival analyses and hazard ratios (HR) were used to determine worsening of renal outcomes. RESULTS Compared with SBP 105–129 mmHg, the risk of ACR worsening increased significantly for SBP 130–139 mmHg (HR 1.88 [95% CI 1.28–2.77]; P = 0.001) and for SBP ≥140 mmHg (2.51 [1.66–3.78]; P < 0.0001). Compared with a PP range of 40–49 mmHg, PP CONCLUSIONS SBP ≥130 mmHg and PP >60 mmHg were associated with worsening ACR. The results suggest that treatment of SBP to

In Brief Diabetic snack bars are formulated to either prevent hypoglycemia or reduce postprandial hyperglycemia. This article reviews this new product category and the evidence-based claims associated with specific products. Diabetes health care providers and their patients should be aware of how products differ based on ingredient formulations and intended uses.

The purpose of this study was to explore possible calculations using oral glucose tolerance test (OGTT) values in order to develop a simple measure of insulin sensitivity. We devised a formula for an insulin sensitivity index, ISI(0,120), that uses the fasting (0 min) and 120 min post-oral glucose (OGTT) insulin and glucose concentrations. It appears to be generalizable across a spectrum of glucose tolerance and obesity. Most importantly, our data show that ISI(0,120) correlates well, when applied prospectively in comparative studies, with the insulin sensitivity index obtained from the euglycemic hyperinsulinemic clamp (r = 0.63, P < 0.001). This correlation was demonstrably superior to other indices of insulin sensitivity such as the HOMA formula presented by Matthews, and performed comparably to the computerized HOMA index. Measurement of insulin sensitivity has traditionally been possible only in research settings because of the invasiveness and expense of the methods used. Clinical investigators have therefore sought more practical methods to obtain an index of insulin sensitivity. Such an index should approximate insulin sensitivity as measured by the euglycemic hyperinsulinemic clamp (M). We present ISI(0,120), a simple yet sensitive measure of insulin sensitivity which is adaptable for use in clinical settings as well as large epidemiologic studies.

Cardiovascular disease (CVD) is the major cause of the morbidity and mortality associated with diabetes in the US. A 2- to 3-fold incidence of CVD occurs in both type 1 and type 2 diabetic individuals over that in age- and gender-matched non-diabetic persons. Recent encouraging data demonstrating a decline in CVD mortality in the general US population do not reflect such a decline in the diabetic population, particularly in women. Increased risk for CVD is related to duration of diabetes and hyperglycemia, as well as hypertension, dyslipidemia, insulin resistance, gender, coagulation abnormalities, and other factors. Health care providers need to advocate for an uncompromising, multi-component attack on all modifiable risk factors for CVD, including glucose control, in the person with diabetes mellitus. This review focuses on known modifiable risk factors for CVD associated with diabetes, potential targets for primary and secondary prevention.

In a previous study, a subgroup of asymptomatic insulin-dependent diabetic individuals (termed IDDM-2) were identified on the basis of diminished parasympathetic cardiac input and elevated heart rate at rest. When compared to another group of asymptomatic IDDM participants (termed IDDM-1), and a nondiabetic healthy control group, the IDDM-2 group displayed elevated blood pressure, supported by elevated total peripheral resistance. Measures of psychological regulation were also taken in this study, and form the basis of this article, which examined whether these IDDM-2 patients differed from the other two groups on these measures. The possible role of glycemic control, IDDM duration, and number of somatic complaints among group differences in psychological regulation was also examined. The IDDM-2 group reported increased psychological distress, as reflected by increased dysphoric or depressive symptoms, trait anxiety, perceived stress, and cynical hostility, as well as decreased optimism and interpersonal, but not family, social support. Glycemic control did not account for any of the group differences in psychological regulation. However, group differences in dysphoria and anxiety were accounted for by differences in somatic complaints, whereas differences in interpersonal social support were accounted for by IDDM duration. Moreover, none of the variables investigated accounted for the diminished optimism of the IDDM-2 group. Therefore, in individuals with IDDM, who would otherwise be considered, after medical examination, as no different from other asymptomatic IDDM individuals, the combination of diminished parasympathetic cardiac input and elevated heart rate was associated with aberrant alterations of both hemodynamic and psychological functioning; the increased psychological distress in these individuals may be influenced, in part, by increased diabetes duration and number of somatic symptoms.

Hermes Florez1†, Jennifer Marks1,2 & Carlos Abraira1,3 †Author for correspondence 1Miami VA Healthcare System GRECC (11GRC), 1201 NW 16th Street, Miami, FL 33125, USA and, University of Miami Miller School of Medicine, Miami, FL, USA Tel.: +1 305 575 3388; Fax: +1 305 575 3365; E-mail: hflorez@ med.miami.edu 2Tel.: +1 305 243 6433; Fax: +1 305 243 3313; E-mail: jmarks@ med.miami.edu 3Tel.: +1 305 575 3585; Fax: +1 305 575 3315; E-mail: cabraira@ med.miami.edu ‘There is clear evidence that use of aspirin, a statin, and the targeted lowering of blood pressure are each associated with substantial reductions in cardiovascular risk in patients with diabetes.’

I began as editor-in-chief of Clinical Diabetes with the first issue of 2003. As I move toward the end of my term, I reflect on various key topics that have come to the forefront in the world of diabetes since then, many of which we have brought to you through these pages. Because this will be the last issue for me and my associate editors, it seems appropriate now to revisit some of the topics that are still relevant, issues that will undoubtedly continue to affect diabetes care in the future. Diabetes in the United States and around the world has reached epidemic proportions, and the numbers are expected to continue to rise. It has been projected that one in three Americans born in 2000 will develop diabetes.1 World-wide, there were 194 million adults with diabetes in 2003, and this number is expected to reach 333 million by 2025, with many cases arising in poorer, developing countries.2 A rise in obesity rates during the past decade is to blame for much of the increase in type 2 diabetes. Today, nearly two-thirds of American adults are overweight or obese.3 In 2005, the American Diabetes Association (ADA), the North American Association for the Study of Obesity (NAASO), and the American Society for Clinical Nutrition (ASCN) jointly published a position statement emphasizing the importance of lifestyle modification in weight management for both the prevention and treatment of type 2 diabetes.4 This effort was directed at making weight management a priority in health care to reverse the …

M any patients and health care providers are unaware that cardiovascular disease (CVD) is the leading cause of death in American women. Because diabetes is a well-established CVD risk equivalent, health care providers in practices that include a significant number of patients with diabetes should be particularly knowledgeable about this and should be able to discuss risks in real terms with their patients. Female patients, especially those with diabetes, should appreciate the magnitude of their own cardiovascular risk and understand what can be done to reduce that risk. Ask a group of women to name a condition they fear and a majority will say breast cancer. Breast cancer awareness has been increasing steadily in the United States in recent years and rightly deserves respect as a killer of women. And, after all, it is the “C” word. But how does it compare with CVD as a cause of mortality in American women? Let's look at some of the facts. 1. In the United States, one in four women has some form of CVD.1 …

Alterations in cardiac autonomic innervation are commonly seen in individuals with diabetes mellitus. In this study, we used a cluster analysis to quantitatively separate individuals with Type I insulin-dependent diabetes mellitus (1DDM) on the basis of assessment of autonomic mediation of resting cardiac function and compared these two IDDM groups with nondiabetic control subjects. One group, termed IDDM-1, exhibited respiratory sinus arrhythmia and resting heart rale (HR) at the same level as controls. A second group, termed IDDM-2, displayed significantly reduced respiratory sinus arrhythmia and elevated resting HR, indicating reduced parasympathetic cardiac input. Noninvasive physiological assessment of the subjects’ response to orthostatic maneuvers (supine, seated, upright tilt) and behavioral stressors (speech preparation, speech talking, mirror tracing, cold pressor) revealed abnormalities in cardiovascular regulation in the IDDM groups. Specifically, under supine resting conditions the IDDM-2 group exhibited reduced myocardial contractility and stroke volume. HR was accelerated in these subjects but not enough to compensate for the decreased stroke volume, and therefore cardiac output was not maintained at normal levels. Consequently, total peripheral resistance and hlood pressure were elevated in thcse subjects. Thus. for the IDDM-2 subjects, these data sugges that blood flow to the periphery is being sacrificed In maintain flow to the heart, lungs, and brain, which cannot sustain themselves anaerobically. The IDDM subjects, when compared with the control subjects, responded with similar magnitude and pattern of cardiovascular response to the behavioral stressors that selectively challenged the heart, vasculature, or both. However, the cardiovascular pattern produced by the IDDM subjects to the seated and uprigh postural challenges suggests that the IDDM-1, and to a certain extent the IDDM-2 subjects, evidenced difficulty in regulating vasomotor and/or venomotor tone to maintain blood pressure levels. Therefore, this study demonstrates a quantitative method for assessing resting parasympathetic status that distinguishes a group of IDDM subjects with abnormal resting cardiovascular regulation and response to challenge.

Diabetes and its complications are a significant cause of morbidity and mortality in the USA. The prevalence of diabetes has been steadily increasing in the adult population, based on national household surveys that were conducted (see Fig. 8.1) [1, 2]. Undiagnosed diabetes and abnormal glucose tolerance are considered to have substantial clinical importance (see Fig. 8.2) [1, 3–6].

Summary Background The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes. Methods In this multicentre, double-blind, randomised controlled trial, patients aged 6–45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375. Findings 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1–112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47–15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept vs 15 [43%] on placebo) or neutropenia (seven [9%] vs five [14%]). Interpretation Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. Funding US National Institutes of Health.

Summary Background Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes. Methods Patients aged 3–45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A 1c (HbA 1c ) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399. Findings 145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349–0·478) in the GAD-alum group, 0·382 nmol/L (0·322–0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351–0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779–1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720–1·13; p=0·50) for GAD-alum plus alum versus alum. HbA 1c , insulin use, and the occurrence and severity of adverse events did not differ between groups. Interpretation Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4–12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. Funding US National Institutes of Health.

Type-I (insulin-dependent) diabetes mellitus is an immunologically mediated disease that results in destruction of the insulin secreting β cells of the pancreas. T cells have been implicated in the pathogenesis of this disease. One novel form of anti-T-cell therapy is the immunoconjugate CD5-Plus®. This agent is composed of the murine IgG 1 monoclonal antibody H65, which is directed toward the CD5+ antigen; and ricin A chain, a ribosomal inhibitor protein. We performed a pilot study to evaluate the safety of the immunoconjugate in subjects with type-I diabetes mellitus. We conducted a dose-escalation study using CD5-Plus given as an intravenous infusion for 5 consecutive days. Fifteen subjects (12 men and 3 women) with a mean age of 26 years, a mean duration of diabetes of 4.8 months, and a minimum stimulated C peptide of 0.3 pmol/mL were entered. Six subjects each were treated at the 0.1 and 0.2 mg/kg/day dosage levels, and three subjects were treated at the 0.33 mg/kg/day dose. Glycemic control was determined monthly by recording the glycohemoglobin, total daily insulin requirements, and fasting blood glucoses. β-cell function was measured by determining the C-peptide response to a mixed formula meal (Sustacal®) at baseline and at 1,3,6,9, and 12 months after treatment. The area under the curve (AUC) of the C-peptide response was calculated and, to reduce variability, related to that of the same subject at baseline. An analysis of subjects who retained at least 80% of their baseline β-cell function as measured by the AUC was performed. In addition, logarithms of the normalized areas under the C-peptide curve (AUC/AUC 0 ) were determined, and the regression line was calculated. This line was compared to that generated by a similar analysis in historical controls who had participated in a previous study using placebo and cyclosporine. T cells were rapidly depleted during the infusion course and recovered to normal values within 30 days. No long-term adverse events were reported. The analysis of subjects retaining 80% of their initial AUC suggested a dose-dependent effect that was significant ( p p

OBJECTIVE This study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS At baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points. RESULTS During a median follow-up duration of 5.2 years, 89 cardiovascular events occurred. Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively). Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC. Subgroup analyses were also conducted for clinically relevant CAC categories: those above and below an Agatston score of 100. Among those randomized to intensive treatment, for the subgroup with CAC >100, 11 of 62 individuals had events, while only 1 of 52 individuals with CAC ≤100 had an event. The multivariable HR for intensive treatment for those with CAC >100 was 0.74 (95% CI 0.46–1.20; P = 0.21), while for the subgroup with CAC ≤100, the corresponding HR was 0.08 (0.008–0.77; P = 0.03), with event rates of 39 and 4 per 1,000 person-years, respectively. CONCLUSIONS These data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis.

The cardiometabolic syndrome (CMS) has been an organizing conceptual framework for subclinical cardiovascular pathophysiology. Using cross-sectional data from 338 healthy men and women aged 18 to 55 years, the study examined the role of central adiposity and insulin sensitivity and assessed potential relationships with other metabolic indices (insulin sensitivity, glucose tolerance, fibrinolysis, lipidemia, endothelial function, and inflammation) and measures of cardiac structure and function (cardiac mass, compliance and contractility, myocardial oxygen demand, and blood pressure). Structural equation modeling analyses, which controlled for sex, age, and race, demonstrated good fit to the data. The derived relationships provided a physiologically consistent model of CMS, with an initiating role for central adiposity and insulin resistance. The model accounted for 30% and 82% of the variance in diastolic blood pressure and myocardial oxygen demand, respectively. The findings suggest predominant pathways through which subclinical metabolic processes may exert pathogenic impact on the heart and vasculature.

Endocrine manifestations of HIV infection include both pathological changes and disturbances in function. Mechanisms include direct infection of glands by HIV or opportunistic organisms, infiltration by neoplasms, side effects of drugs, and production of humoral factors that may alter metabolism. The adrenal gland is most often affected, but virtually every endocrine system may be involved. Dysfunction is often subtle, with symptoms overlapping those of the HIV infection itself. Endocrine manifestations may be found at any time in the course of the disease, from the asymptomatic HIV-positive stage through full-blown AIDS. Optimal management of these patients may include a careful search for, and appropriate treatment of, associated endocrine abnormalities.

In this Practice Point commentary, I describe the findings and limitations of a 52-week, open-label, noninferiority, head-to-head comparison study of the basal insulin analogs detemir and glargine. Rosenstock et al. enrolled 582 insulin-naive individuals with type 2 diabetes mellitus inadequately controlled with oral antidiabetic agents. Participants were randomly allocated to receive either detemir or glargine, titrated to a target fasting plasma glucose level

Diabetes mellitus (DM) is actually a group of metabolic disorders characterized by hyperglycemia which can result from defects in insulin secretion, insulin action, or both. Chronic hyperglycemia is associated with the development of damage to various organs in the body – the eyes, kidneys, nervous system, and cardiovascular system.DM and its complications constitute a significant public health problem worldwide, and are an important cause of morbidity and mortality. In fact, DM has reached epidemic proportions throughout the world, and the prevalence numbers are expected to continue to rise. Worldwide there were 194 million adults with DM in 2003, and this number is expected to reach 333 million by the year 2025, with many cases developing in poorer, developing countries.1 A rise in obesity rates over the past decade is to blame for much of the increase in type 2 DM. Today, nearly two-thirds of US adults are overweight or obese.2 It has been projected that one in three US citizens born in 2000 will develop DM.3

Compare the efficacy, safety, and patient satisfaction of continuous subcutaneous insulin infusion (CSII) therapy with multiple daily injection (MDI) therapy for patients with type 2 diabetes.A total of 132 CSII-naive type 2 diabetic patients were randomly assigned (1:1) to CSII (using insulin aspart) or MDI therapy (bolus insulin aspart and basal NPH insulin) in a multicenter, open-label, randomized, parallel-group, 24-week study. Efficacy was assessed with HbA(1c) and eight-point blood glucose (BG) profiles. Treatment satisfaction was determined with a self-administered questionnaire. Safety assessments included adverse events, hypoglycemic episodes, laboratory values, and physical examination findings.HbA(1c) values decreased similarly for both groups from baseline (8.2 +/- 1.37% for CSII, 8.0 +/- 1.08% for MDI) to end of study (7.6 +/- 1.22% for CSII, 7.5 +/- 1.22% for MDI). The CSII group showed a trend toward lower eight-point BG values at most time points (only significant 90 min after breakfast; 167 +/- 48 vs. 192 +/- 65 mg/dl for CSII and MDI, respectively; P = 0.019). A total of 93% of CSII-treated subjects preferred the pump to their previous injectable insulin regimen for reasons of convenience, flexibility, ease of use, and overall preference. Safety assessments were comparable for both treatment groups.Insulin aspart in CSII therapy provided efficacy and safety comparable to MDI therapy for type 2 diabetes. Patients with type 2 diabetes can be trained as outpatients to use CSII and prefer CSII to injections, indicating that pump therapy should be considered when initiating intensive insulin therapy for type 2 diabetes.

Maintaining glycemic and metabolic control is difficult in diabetic patients who are undergoing surgery. The preoperative evaluation of all patients with diabetes should include careful screening for asymptomatic cardiac or renal disease. Frequent self-monitoring of glucose levels is important in the week before surgery so that insulin regimens can be adjusted as needed. Oral agents and long-acting insulin are usually discontinued before surgery, although the newer long-acting insulin analog glargine may be appropriately administered for basal insulin coverage throughout the surgical period. The usual regimen of sliding scale subcutaneous insulin for perioperative glycemic control may be a less preferable method because it can have unreliable absorption and lead to erratic blood glucose levels. Intravenous insulin infusion offers advantages because of the more predictable absorption rates and ability to rapidly titrate insulin delivery up or down to maintain proper glycemic control. Insulin is typically infused at 1 to 2 U per hour and adjusted according to the results of frequent blood glucose checks. A separate infusion of dextrose prevents hypoglycemia. Potassium is usually added to the dextrose infusion at 10 to 20 mEq per L in patients with normal renal function and normal preoperative serum potassium levels. Frequent monitoring of electrolytes and acid-base status is important during the perioperative period, especially in patients with type 1 diabetes because ketoacidosis can develop at modest levels of hyperglycemia.

The purpose of this study was to examine characteristics associated with the insulin metabolic syndrome, including insulin resistance, abnormal glucose tolerance, dyslipidemia, obesity, and elevated blood pressure, among women who have experienced gestational diabetes. 39 nondiabetic, young (20–42 years), postpartum (3–18 months) white women were recruited from obstetrical clinics. Twenty-one women had a history of gestational diabetes; 18 had uncomplicated pregnancies. Multivariate analyses revealed a significant difference between groups in insulin resistance (M, measured by euglycemic clamp) and insulin levels (from an oral glucose tolerance test), with insulin resistance showing a statistically stronger difference than insulin levels. Groups also differed significantly when compared on a set of variables associated with insulin metabolic syndrome: glucose tolerance, triglycerides, blood pressure, and body-mass index. Using insulin resistance as a covariate eliminated these group differences, suggesting that insulin resistance is the key factor underlying insulin metabolic syndrome. The higher risk of later developing type 2 diabetes and hypertension in women who have a history of gestational diabetes is explicable by their poorer profile on variables associated with insulin metabolic syndrome, and appears to be attributable to insulin resistance. Thus, insulin resistance appears to distinguish young women at risk for cardiovascular disease.

The treatment of the patient with diabetes, with or without hypertension, is complex and challenging. Hyperglycemic treatment should ideally not only control blood glucose, but also prevent the chronic complications and associated metabolic derangements that can lead to increased morbidity and mortality. Hypertensive treatment should not only decrease blood pressure, but also reduce the risk of macrovascular and microvascular disease. The use of antihypertensive agents that improve insulin resistance, dyslipidemia, glycemic control, and nephropathy is preferred whenever possible. The real key to success in the care of the hypertensive diabetic patient is adequate screening and appropriate, early treatment. Currently, there is ample evidence to support the use of intensive management with the goal of near-normalization of blood glucose levels in most patients with diabetes. Similarly, aggressive treatment of hypertension is the current standard. Accomplishing these goals helps to prevent the development of chronic diabetic complications, including nephropathy. ESRD need not be the inevitable outcome for individuals with early diabetic nephropathy. Interventions currently available that are targeted at the known modifiable risk factors underlying the development and progression of diabetic nephropathy offer the best hope for reducing the incidence and severity of this complication. Prevention of the complications of diabetes, including nephropathy, must be the goal for the future on behalf of all those who now have diabetes.

T.R., an obese 40-year-old African-American man with a medical history significant for hypertension, presented to the emergency department complaining of 5 days of weakness, abdominal pain, and upper respiratory symptoms. On further questioning, he also reported ∼ 1 month of polyuria, polydipsia, and polyphagia accompanied by a 5-lb weight loss. No visual symptoms were noted. His medical history included hypertension with antihypertensive noncompliance, an exploratory laparotomy for a gunshot wound, and a remote appendectomy. He denied the use of alcohol, tobacco, or illicit drugs. His family history was strongly positive for adult-onset diabetes, including one sibling who died of related complications. On initial physical examination, he was afebrile, with a blood pressure of 140/90 mmHg and a heart rate in the 120 bpm range. Physical findings were remarkable for abdominal obesity and acanthosis nigricans. Arterial blood gas revealed a pH of 7.31 and partial pressure of carbon dioxide of 22 and bicarbonate of 3. Serum chemistries revealed the following: serum sodium 144 mEq/l, potassium 6.9 mEq/l, bicarbonate 7 mEq/l, blood urea nitrogen 50 mg/dl, and creatinine 3.5 mg/dl. Serum glucose was 1,200 mg/dl. Serum acetone was detectable in moderate quantity. C-peptide was nondetectable. Urinalysis demonstrated glycosuria with moderate ketones and negative protein. Complete blood count was consistent with hemoconcentration and otherwise unremarkable. Amylase, lipase, and thyroidstimulating hormone were within normal limits. Hemoglobin A1c (A1C) was 13.6%, and antibodies to GAD-65 were not detected. Myocardial ischemia and infectious processes were excluded. T.R. was initially admitted to the …

A s pointed out in this issue's commentary by K.M. Venkat Narayan, MD, MPH, FRCP, FACP (p. 38), the association of several cardiovascular disease (CVD) risk factors—central obesity, hypertension, dys-lipidemia, and abnormalities of glucose regulation—and their assumed interrelatedness with insulin resistance have led many experts in the field to link them into a distinct entity referred to as “metabolic syndrome.” Much debate exists as to whether the identification of these risk factors as a “syndrome” is useful in terms of improved detection and earlier treatment aimed at reducing CVD risk. As noted in the Narayan commentary, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have published a joint position statement recommending against its identification as such and have raised important concerns about its therapeutic value. I refer you to our commentary, as well as the complete joint statement simultaneously published in Diabetes Care 1 and Diabetologia .2 There are many …

W e are all going to die; I think we would all prefer to die with dignity. Not too long ago, the country watched the anguish of family members of Terri Schiavo torn apart over prolonging her life or allowing her death. Their very public suffering was certainly not what any of us would want our relatives to face, nor would we want to find ourselves a grieving family member in a public spectacle such as that which surrounded this woman's death. The courts are the last place such issues should be decided. Ideally, they should be decided by each individual for him- or herself. The right of competent adult Americans to refuse unwanted medical intervention is well established. The Patient Self-Determination Act of 1990 clearly put forth the right of every patient's control over end-of-life care, assuming that the choices would be fully informed.1 One hopes that we, as health care providers, …

D espite affecting as many as 50% of all diabetic individuals, diabetic peripheral neuropathy (DPN) is the chronic complication that is often least addressed by health care providers. This is partly because of the experience many of us have shared of having little success with its treatment and because of a lack of awareness of available treatment strategies. Yet lack of knowledge is not an acceptable reason for failing to address this problem aggressively. Although many serious chronic complications affect people with diabetes, foot complications are the greatest burden. As many as 40-60% of lower extremity amputations (LEAs) are related to DPN.1 In the United States, more than 50,000 …

In case you haven't noticed, low-carb diets have become the rage. Suddenly, the low-carb “lifestyle” (whatever that means) is in. Fat is fine! Eat all the bacon and steak you want, but don't touch that pasta! Unless, of course, you bought low-carb pasta at one of those new low-carb food stores. Entire stores full of “carb alternatives” and “smart-carb” foods have arisen. And the number of diet books pushing variations of the low-carb diet is growing yearly. We have seen the enemy, and it is the carbohydrate. But do people make healthy food choices by focusing solely on cutting carbs? I recently had lunch with a friend who is watching his weight. His order? “Double cheeseburger, hold the bun.” It makes no sense. A double cheeseburger is conservatively 1,000 kcal, whereas a single cheeseburger with a bun is perhaps 600. …

While Americans grow fatter, insurers' coverage of weight loss surgery is shrinking. The Centers for Disease Control and Prevention warns that obesity is poised to become the leading cause of mortality in the United States by 2005.1 Yet, this surgical treatment option for the one in fifty Americans who have a BMI of 40 kg/m2 or more—or are more than 100 lb overweight—is being trimmed. Insurers claim they cannot afford to pay for surgery that they believe to be risky. Bariatric procedures have a mortality rate of 0.3%, which may be on the …