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Background: This study was performed to characterize the long-term safety and efficacy of inhaled human insulin (EXU; Exubera (insulin human [rDNA origin]) Inhalation Powder). Scope: Patients with type 1 or type 2 diabetes (N=1290) who had successfully completed one of six controlled EXU open-label trials elected to receive open-label treatment with EXU for up to 3 years, after which they were randomized to discontinue EXU or to continue therapy for 6 months, then discontinue. Immunologic safety was assessed by insulin antibody (IAb) binding, and pulmonary safety was assessed by tests for forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusing capacity (DLCO). In addition, changes over time in IAbs were compared with changes in FEV1, DLCO, hypoglycemia, and efficacy. Findings: Antibody binding increased in patients with either type 1 or type 2 diabetes after initiation of EXU and plateaued within 6-12 months (increases were higher in patients with type 1 diabetes than in patients with type 2 diabetes). Decreases in FEV1 occurred primarily during the first 3-6 months of EXU therapy. Among adult patients in the All Subjects set, the mean (±SE) annualized rate of decline in FEV1 was -0.053±0.007 liters/year (95% CI, -0.065, -0.040) in adult patients with type 1 diabetes, and -0.076±0.005 liters/year (95% CI, -0.085, -0.067) in patients with type 2 diabetes. Changes in DLCO occurred primarily during the first 3-6 months of EXU therapy. Among adult patients, in the All Subjects set, the mean (±SE) annual decline in DLCO was -0.738±0.097 mL/min/mmHg/year (95% CI, -0.927, -0.548) and -0.688±0.082 mL/min/mmHg/year (95% CI, -0.849, -0.527) in patients with type 1 and type 2 diabetes, respectively. Antibody binding did not correlate with changes in glycemic control, lung function, dose, or hypoglycemia. Following discontinuation of EXU, IAbs decreased to near baseline levels. Conclusion: These results are consistent with other trials showing long-term maintenance of safety and efficacy of EXU despite insulin antibody formation and small treatment group differences in pulmonary function. A limitation of the study was the lack of a comparator therapy. [ABSTRACT FROM AUTHOR]

Objective: To determine, for individuals with type 2 diabetes and microalbuminuria, the effects of 6 weeks of meals containing plant-based protein (PP) versus meals with predominantly animal-based protein (AP) on renal function and secondarily on glycemia, lipid levels, and blood pressure.Research Design and Methods: In a randomized crossover trial, we compared 6 weeks of meals containing only PP with meals containing primarily AP (60% animal, 40% plant) in 17 subjects with type 2 diabetes and microalbuminuria treated with diet and/or oral antidiabetic agents. Protein content was equivalent to the average American diet, and calories provided weight maintenance. Nutrients were equivalent between the two diets. Meals were prepared and packaged by a metabolic kitchen staff and were sent home weekly. At the beginning and end of each 6-week period, subjects were studied for 36 h on a metabolic unit.Results: There were no significant differences between diets for glomerular filtration rate, renal plasma flow, albumin excretion rate, total cholesterol, HDL cholesterol, triglyceride area under the curve (AUC), glucose and insulin AUC, HbA(1c,) blood pressure, or serum amino acids. For both diets, at the end of the treatment periods as compared with baseline, total cholesterol was significantly lower (PP and AP: from 4.75 to 4.34 mmol/l, P < 0.01), HbA(1c) had significantly improved (PP: from 8.1 to 7.5%, P < 0.01; AP: from 7.9 to 7.4%, P < 0.01), and diastolic blood pressure was significantly lower (PP: from 83 to 80 mmHg, P < 0.02; AP: from 82 to 78, P < 0.02).Conclusions: There is no clear advantage for the recommendation of diets containing only PP rather than diets containing protein that is primarily animal-based for individuals with type 2 diabetes and microalbuminuria. There are, however, potential lipid, glycemic, and blood pressure benefits for following a carefully constructed, weight-maintaining, healthy diet, regardless of protein source. [ABSTRACT FROM AUTHOR]

Regardless of purity and origin, therapeutic insulins continue to be immunogenic in humans. However, severe immunological complications occur rarely, and less severe events affect a small minority of patients. Insulin autoantibodies (IAAs) may be detectable in insulin-naive individuals who have a high likelihood of developing type 1 diabetes or in patients who have had viral disorders, have been treated with various drugs, or have autoimmune disorders or paraneoplastic syndromes. This suggests that under certain circumstances, immune tolerance to insulin can be overcome. Factors that can lead to more or less susceptibility to humoral responses to exogenous insulin include the recipient's immune response genes, age, the presence of sufficient circulating autologous insulin, and the site of insulin delivery. Little proof exists, however, that the development of insulin antibodies (IAs) to exogenous insulin therapy affects integrated glucose control, insulin dose requirements, and incidence of hypoglycemia, or contributes to beta-cell failure or to long-term complications of diabetes. Studies in which pregnant women with diabetes were monitored for glycemic control argue against a connection between IAs and fetal risk. Although studies have shown increased levels of immune complexes in patients with diabetic microangiopathic complications, these immune complexes often do not contain insulin or IAs, and insulin administration does not contribute to their formation. The majority of studies have shown no relationship between IAs and diabetic angiopathic complications, including nephropathy, retinopathy, and neuropathy. With the advent of novel insulin formulations and delivery systems, such as insulin pumps and inhaled insulin, examination of these issues is increasingly relevant.

Background and Methods: Delivery of insulin to the deep lung presents unique challenges to the body's mucosal defense system. Pulmonary mucosal defense has the ability to discriminate between self and non-self antigens and has the potential for induction of immunologic tolerance. Published data concerning the immunogenicity of inhaled human insulin in drug trials will be reviewed, and data regarding the possible adverse effects of anti-insulin antibody development will be presented. Examination of the immunologic safety of inhaled human insulin will include discussion of comparator studies, factors affecting immunogenicity, the effects of insulin immunity on glycemic control and pulmonary function, and the relationship of insulin antibodies to dose requirements, pharmacodynamics, and hypoglycemia., Conclusions: Inhaled human insulin, whether formulated as a powder or liquid, has been shown to be more immunogenic than comparator insulins given by subcutaneous routes; however, adverse effects of antibody formation have not been demonstrated.

Peptides are a growing class of agents whose therapeutic use originated with non-human treatments such as animal insulins. Xenopeptides continue to be explored for biotherapeutic development using genetic engineering, and through the rich resource of animal and plant polypeptides. One of the major concerns of therapeutic administration of xenopeptides is the potential for untoward immune responses that may lead to loss of drug efficacy or adverse events in recipients. An increased risk of immunogenicity is perceived with xenopeptides, however, human-derived therapies also induce antibody formation that in some cases has been associated with severe clinical sequelae. In this review, antibody responses to xenopeptides are highlighted looking at current hormone therapies used to treat endocrine disorders. Similar to clinical experiences with peptide-based agents in general, antibody responses against xenopeptide hormone therapies in majority of cases have been benign in nature with minimal clinical impact.

Administration of insulin by inhalation was first attempted > 50 years ago. At that time, little was known concerning effective delivery systems and insulin formulations. The recent development of pulmonary delivery systems for the administration of insulin is driven by the reluctance of patients and their providers to initiate insulin earlier in the course of Type 2 diabetes, the desire to reduce the number of daily insulin injections for both Type 1 and 2 patients, and the recent emphasis on intensified glycaemic control including postprandial glycaemic control. The deep lung is a unique mucosal tissue having a surface area of > 100 m2 and is readily accessible both to the external environment and to drug delivery, provided that appropriate conditions are met. There have been four mid- to late-phase pulmonary insulin programmes using modern inhalation devices that will be reported in this paper. The programmes differ in the choice of delivery systems, the formulations of insulin and reported bioavailability, pharmacokinetic and glucodynamic profiles and adverse events. However, all systems successfully deliver insulin to the deep lung and biological effectiveness compares favourably with injected subcutaneous insulins.

Objective: To compare antibody responses to inhaled human insulin vs. sc human insulin and to determine whether insulin antibody binding is associated with adverse clinical consequences., Research Design and Methods: Insulin antibody data from initial phase II/III trials were analyzed comparing the efficacy and safety of inhaled insulin with various agents, including sc insulin. Additionally, data from a 24-month extension of the phase III studies were examined. Data were pooled into the following three groups based on insulin treatment status at baseline: patients with type 1 diabetes, and patients with type 2 diabetes using insulin and not using insulin at baseline. Ig class analysis was also performed on randomly selected sera from type 1 patients at the end of the initial trials., Results: In the initial trials, greater insulin antibody binding was observed in patients receiving inhaled insulin vs. sc insulin. The greatest antibody responses to inhaled insulin were observed in patients with type 1 diabetes [nonparametric comparison of medians at the end of the study, 22.0% binding (unadjusted 95% confidence interval: 19.5, 24.5)], and the lowest responses were observed in non-insulin-using patients with type 2 diabetes in which there was no difference in median values at the end of the study. There were no correlations between antibody binding and glycemic control (measured using glycosylated hemoglobin), insulin dose requirements, hypoglycemic events, or pulmonary function (measured by changes in forced expiratory volume in 1 sec and diffusion capacity of carbon monoxide). Antibody responses were IgG in type. Differences in antibody levels observed in patients with type 1 vs. type 2 diabetes were maintained over the 24-month extension trials. Peak antibody levels across all groups were generally observed after 6-12 months of insulin therapy. Inhaled insulin therapy was not associated with a greater incidence of allergy or other hypersensitivity reactions., Conclusion: Inhaled insulin was observed to produce a larger antibody response than sc insulin. Insulin antibody binding has not been associated with adverse clinical consequences in trials to date.

Objective: To determine the long-term effects of insulin lispro on inducing lispro-specific, insulin-specific, and cross-reactive (reactive with both insulin lispro and human insulin) antibodies., Research Design and Methods: A multinational, multicenter combination of controlled and noncontrolled, open-label studies of 4.5 years' duration was designed to evaluate the long-term immunologic profile of subcutaneously administered insulin lispro. A total of 1,221 patients (men and women; 12-81 years of age) with type 1 or type 2 diabetes were enrolled. Circulating anti-insulin antibodies were measured using radioimmunoassays., Results: Insulin-specific and lispro-specific antibody responses were within the background noise levels of the assays. Significant elevations of antibody were confined to a cross-reactive antibody response. Antibody levels resulting from prior exposure to long- and short-acting insulins changed little after transfer to insulin lispro and remained within or near the baseline levels. De novo exposure to insulin lispro resulted in increases in cross-reactive but not insulin- or lispro-specific antibody levels. Cross-reactive insulin antibodies developed more readily in patients with type 1 diabetes than in those with type 2 diabetes. Long-term antibody responses tended to decrease over time and returned to baseline or near-baseline levels by the end of the long-term studies. No evidence of an anamnestic antibody response could be found in individuals treated intermittently with insulin lispro., Conclusions: The immunogenic profile of patients treated with insulin lispro was comparable to that of patients treated with recombinant human insulin. Inductions of significant levels of specific or cross-reactive antibodies were not observed in patients who had received insulin previously. No significant antibody-dependent increases in insulin dosage requirements were noted in these patients. The incidence of insulin allergy was not different from that in patients treated with recombinant regular human insulin.

Background: Hyperglycemia during acute ischemic stroke may augment brain injury, predispose to intracerebral hemorrhage (ICH), or both., Method: To analyze the relationship between admission glucose level and clinical outcomes from acute ischemic stroke, the authors performed multivariate regression analysis with the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) Stroke Trial data. Neurologic improvement was defined as improvement on the NIH Stroke Scale by 4 or more points from baseline to 3 months, or a final score of zero. Favorable outcome was defined as both Glasgow Outcome score of 1 and Barthel Index 95 to 100 at 3 months. Symptomatic ICH was defined as CT-documented hemorrhage temporally related to clinical deterioration within 36 hours of treatment. Potential confounding factors were controlled, including acute treatment (rt-PA or placebo), age, baseline NIH Stroke Scale score, history of diabetes mellitus, stroke subtype, and admission blood pressure., Results: There were 624 patients enrolled within 3 hours after stroke onset. As admission glucose increased, the odds for neurologic improvement decreased (odds ratio [OR] = 0.76 per 100 mg/dL increase in admission glucose, 95% CI 0.61 to 0.95, p = 0.01). The relation between admission glucose and favorable outcome depended on admission mean blood pressure (MBP): as admission MBP increased, the odds for favorable outcome related to increasing admission glucose levels progressively decreased (p = 0.02). As admission glucose increased, the odds for symptomatic ICH also increased (OR = 1.75 per 100 mg/dL increase in admission glucose, 95% CI 1.11 to 2.78, p = 0.02). Admission glucose level was not associated with altered effectiveness of rt-PA., Conclusions: In patients with acute ischemic stroke, higher admission glucose levels are associated with significantly lower odds for desirable clinical outcomes and significantly higher odds for symptomatic ICH, regardless of rt-PA treatment. Whether this represents a cause and effect relationship remains to be determined.

We conducted noninvasive measures of vascular compliance and glucose tolerance in 275 normotensive and hypertensive subjects. Of the total, 194 (70.5%) were hypertensive, 73 (26%) diabetic, 7 (2.5%) normotensive and diabetic and 66 (24%) both hypertensive and diabetic, and 74 (27%) normotensive and nondiabetic. In addition, 57 of the nondiabetic subjects had impaired glucose tolerance based on the results of blood glucose levels 2 h after a glucose challenge. For the entire population, large artery compliance was correlated with systolic (P < .001), diastolic (P = .041), and pulse (P < .001) pressures, whereas small artery compliance correlated significantly (P < .001) only with systolic and pulse pressures. Among hypertensives, a significant decrease in large and small vessel compliance was seen, which was reduced further in the case of small vessel compliance by the presence of diabetes. When the population was separated on the basis of glucose tolerance into normal, impaired, and diabetic groups, a progressive reduction (P < .001) in small artery compliance was seen that was independent of age. Similar significant (P < .001) progressive increases in body mass index and systolic pressure were seen with progression of carbohydrate intolerance. These findings confirm the close relationship between elevated blood pressure (BP) and carbohydrate intolerance and indicate that the vascular effects of both are separate, additive, and primarily on small blood vessel compliance. These findings have important implications for the preclinical detection and potential prevention of hypertension, diabetes, and associated vascular disease.

Background: Hyperglycemia at the time of acute ischemic stroke has been linked to worse outcome in both human and animal studies., Objective: To describe the prevalence and severity of hyperglycemia on hospital admission among acute ischemic stroke patients, to examine the independent relationship of admission hyperglycemia to all-cause mortality, and to document the inpatient management of hyperglycemia., Methods: Patients hospitalized with acute ischemic stroke at one hospital from July 1993 to June 1998 (n = 656) were identified. Demographic data, diagnoses, and blood glucose (BG) values were retrieved from the electronic medical record system. Admission stroke severity, fingerstick BG results, and new diabetes diagnoses were obtained by chart review. Hyperglycemia was defined as admitting random serum BG > or = 130 mg/dL. Hazard ratios (HR) for 30-day, 1-year, and 6-year mortality were calculated using multivariable Cox regression models., Results: Hyperglycemia at admission to hospital was present in 40% of patients with acute stroke. Patients with hyperglycemia were more often women and more likely to have prior diagnoses of diabetes and heart failure. Almost all of these patients remained hyperglycemic during their hospital stay (mean BG = 206 mg/dL), and 43% received no inpatient hypoglycemic drugs. Hyperglycemic patients had longer hospital stay (7 vs 6 days, p = 0.015) and higher inpatient hospital charges ($6,611 vs $5,262, p < 0.001). Hyperglycemia independently increased the risk for death at 30 days (HR 1.87, p < or = 0.01), 1 year (HR 1.75, p < or = 0.01), and 6 years after stroke (HR 1.41, p

Background: Although a variety of factors have been shown to influence vascular compliance in humans, few studies have been large enough to adequately assess the effects of age, race, gender, blood pressure (BP), and estrogen therapy., Methods: As part of a long-term follow-up study, 272 subjects, 50% women, 26% African American, 71% currently hypertensive, ranging in age from 33 to 80 years were studied with noninvasive measures of vascular compliance by pulse wave analysis., Results: A significant age-related decrease in large and small vessel compliance and increase in vascular resistance and impedance was seen in all hypertensive subjects and in normotensive women. The slope of the relationship was significantly steeper for women than for men. No effect of estrogen or race could be observed. In hypertensive subjects, pulse pressure exerted an effect similar to that of age., Conclusions: Studies of vascular compliance must consider a variety of demographic and physiologic factors including age, gender, and BP. Race and estrogen administration do not appear to contribute to the variables independent of the factors identified.

We evaluated a multistep protocol to locate and ascertain data from 708 subjects who participated in clinical studies at our medical center up to 27 years ago. The protocol involved computerized and manual chart audits, introductory letters, internet searches, death registries, and a commercial person locator. We were able to ascertain vital status on 596 (84%) of study participants. Moreover, of the 475 persons known to be alive, 426 (90%) returned questionnaires and 275 (58%) completed physical examination and laboratory studies in our Clinical Research Center. The relatively modest cost of the protocol ($53,426) suggests that it is a reasonable strategy to test hypotheses involving long-term outcomes among well-characterized cohorts. The fact that the protocol can be easily implemented in most sites should encourage investigators to use these strategies to conduct similar studies.

Objective: To evaluate the accuracy, comfort, and ease of use of a new automated device for blood glucose monitoring using the arm as an alternative sampling site., Research Design and Methods: These studies use an automated hand-held device that applies a small vacuum, lances the skin, transfers blood onto an electrochemical test strip, and measures glucose. Patients who had type 1 or type 2 diabetes and had received no prior training using this device were recruited from five diabetes clinics. Testing was performed by the patients using this device and by trained healthcare professionals. Blood glucose was measured by 354 patients: from the arm using the device, from the finger using a laboratory reference instrument, and from the finger using the device via the secondary test port. Each patient completed a questionnaire rating the level of pain and ease of use of the device., Results: Blood glucose results in samples obtained from the arm with the automated device agreed well with finger-stick plasma glucose results using a reference instrument (regression slope 0.98, intercept 0.01 mmol/l [0.1 mg/dl], r = 0.96). Error grid analysis showed that 100% of the measurements fell within zones A and B. In the survey, 60% of the patients reported that arm testing with the automated device was "painless;" another 31% of the patients stated that it was "much less painful," and 6% of patients considered using the device "less painful" than finger-stick testing. In a survey containing 15 questions for rating the ease of use with a scale of 1 to 6, the overall mean rating was 5.5., Conclusions: The automated device is easy to use and provides accurate glucose results; 97% of the patients found it less painful than finger-stick testing.

Although factors such as age, blood pressure, and its responsiveness to changes in sodium balance and extracellular fluid volume status (salt sensitivity) are associated with an increased risk of end-organ disease and cardiovascular events in hypertensive subjects, no such relationship with mortality has been demonstrated for salt sensitivity in normotensive subjects. We conducted long-term follow-up of 430 normal and 278 hypertensive subjects in whom assessment of salt sensitivity of blood pressure was performed as long as 27 years ago. We ascertained the status of 596 subjects (85% of the total population), 123 (21%) of whom had died. The following initial measurements were significantly (P<0.002) associated with subjects who had died compared with subjects known to be alive: age at study, pulse pressure, systolic, diastolic, and mean arterial pressures, hypertension, salt sensitivity, baseline renin levels, and body mass index (but not body weight). A stepwise logistic regression found the following independent predictors of death (odds ratio, 95% CI): age at initial study (1.08, 1.06 to 1.10), baseline blood pressure (1.03, 1.01 to 1.04), sodium sensitivity (1.73, 1.02 to 2.94), and male gender (1.91, 1.15 to 3.17). When survival curves were examined, normotensive salt-sensitive subjects aged >25 years when initially studied were found to have a cumulative mortality similar to that of hypertensive subjects, whereas salt-resistant normotensive subjects had increased survival (P:<0.001). These observations provide unique evidence of a relationship between salt sensitivity and mortality that is independent of elevated blood pressure.

Despite evidence that supports the beneficial effects of postmenopausal hormone replacement therapy (HRT), concerns remain about its possible adverse effects. However, entry into the postmenopausal state is associated with many characteristics of the insulin resistance syndrome, including increased cardiovascular morbidity and mortality, accretion of generalised and visceral adiposity and insulin resistance. Studies carried out in postmenopausal women have revealed that an increase in visceral obesity is associated with an increase in androgenicity that, in turn, is associated with type 2 (non-insulin-dependent) diabetes mellitus. Short term studies of HRT containing conjugated estrogens (CEE) and medroxyprogesterone (MPA) have shown prevention of the accretion of visceral fat. However, longer term studies using other techniques suggest that these effects may be evanescent. A few trials suggest that oral estrogen therapy reduces postmenopausal insulin resistance, as suggested by reductions in fasting insulin and glucose levels and an increase in glucose metabolism rates, whereas most studies do not show an adverse effect upon carbohydrate metabolism. MPA may decrease these beneficial effects. Transdermal estrogen is essentially neutral with regard to insulin sensitivity and oral estradiol (17beta-estradiol) may also be neutral or enhance sensitivity. Different progestogens vary in their effects upon carbohydrate metabolism. The Postmenopausal Estrogen/Progestogen Intervention (PEPI) Study was a prospective, 3-year, randomised trial in 875 women that compared placebo, unopposed CEE, CEE plus continuous MPA, CEE plus cyclical MPA, and CEE plus cyclical micronised progesterone. Fasting insulin and glucose levels decreased significantly by 16.1% and 0.122 mmol/L, respectively, in all drug treatment groups. However, after a 75g glucose load, glucose levels at 2 hours increased by 0.33 mmol/L in the active treatment groups without a corresponding increase in insulin levels. No beneficial effects on waist/hip ratio could be demonstrated. Data from the PEPI trial also suggested that the maximum benefit regarding carbohydrate metabolism was achieved in patients who were the most hyperglycaemic and hyperinsulinaemic at the start of therapy. It can be concluded, therefore, that HRT has few, if any, harmful effects on carbohydrate metabolism and that it may be of benefit in women in modifying the long term complications of the postmenopausal state.

The relationship between macrovascular complications of diabetes mellitus, hypertension, and dyslipidemia is explored. Management strategies for patients with lipid abnormalities are given, along with indications and use of available drug classes. Pharmacologic and nonpharmacologic approaches to hypertension management are reviewed. The controversies concerning the use of various classes of anti-hypertensive drugs including calcium channel blockers and diuretic therapy are also discussed.

Objective: To assess the efficacy of unopposed estrogen, and three estrogen/progestin regimens on selected heart disease risk factors among adherent women and to contrast those results with efficacy among all women in the PEPI study., Design: A 3-year, multicenter, randomized, double-blinded, placebo-controlled clinical trial., Participants: A total of 847 healthy postmenopausal women aged 45 to 64 years of age with no known contraindication to hormone therapy, who attended their 36 month clinical visit., Intervention: Participants were randomized in equal numbers to one of the following treatments: (1) placebo; (2) conjugated equine estrogen (CEE) 0.625 mg daily; (3) CEE 0.625 daily plus medroxyprogesterone acetate (MPA) 10 mg, days 1-12; (4) CEE 0.625 daily plus MPA 2.5 mg daily; or (5) CEE 0.625 daily plus micronized progesterone (MP) 200 mg, days 1-12., Analysis: Analyses are based on adherent women, where adherence is defined as taking at least 80% of pills at each 6-month visit., Results: Adherence rates were high in all groups except women with a uterus assigned to unopposed CEE. The difference in HDL-C levels resulting from the CEE vs. CEE+MP was approximately three times larger than in the intent-to-treat analyses, reaching statistical significance (P < 0.05). In each active treatment, LDL-C decreased 10-15%. Triglycerides increased 15-20% in each opposed CEE arm and over 25% in the CEE only arm; this difference was not statistically significant. Fibrinogen increased by 7% among placebo adherers, but decreased or remained fairly stable among the active arm adherers. Systolic blood pressure increased 3-5% in all treatment arms. Women adherent to the CEE+MPA arms had twice the increase of 2 h glucose levels as women adherent to CEE only, or CEE+MP (8-9% vs. 3-4%). Two-hour insulin levels decreased 3-12% for all arms. The patterns of change for fibrinogen, SBP, 2 h glucose and insulin were similar to those from the intent-to-treat analyses., Conclusions: In analyses limited to adherent women, all active treatments, compared to placebo, continued to have similar and favorable effects on LDL-cholesterol and fibrinogen and no significant effects on blood pressure or insulin levels. Given the overall high adherence rates in PEPI, the results are similar to the intent-to-treat analyses, as expected. Only the trend of HDL-C to have a larger increase in the CEE only arm (in the intent-to-treat analyses) gained statistical significance in analyses restricted to adherers.

Reports from cross-sectional comparisons, nonrandomized prospective studies, and relatively small clinical trials indicate that postmenopausal hormone therapy may slightly decrease the amount of weight typically gained by women during the decade following menopause. Despite this, widespread belief remains that hormone therapy may cause weight gain. We use data from the Postmenopausal Estrogen/Progestin Interventions trial to characterize the impact of postmenopausal hormone therapy on weight and fat distribution and to examine the consistency of this impact among subgroups of women defined by lifestyle, clinical, and demographic factors. The Postmenopausal Estrogen/Progestin Interventions trial was a 3-yr, placebo-controlled, randomized clinical trial of 875 women assessing the effects on cardiovascular risk factors of four hormone regimens: oral conjugated equine estrogen (CEE) therapy (0.625 mg daily alone), CEE in combination with medroxyprogesterone acetate (2.5 mg daily), CEE in combination with medroxyprogesterone acetate (10 mg daily on days 1-12), and CEE in combination with micronized progesterone (200 mg daily on days 1-12). Women randomly assigned to CEE with or without a progestational agent averaged 1.0 kg less weight gain at the end of 3 yr (P = 0.006) than those assigned to placebo. Assignment to CEE was also associated with averages of 1.2 cm less increase in waist girth (P = 0.01) and 0.3 cm less increase in hip (P = 0.07) girth. In regression models that included weight change as a covariate, none of these differences reached statistical significance. There were no significant differences in weight or girth changes among any of the four active hormone regimens. After accounting for the effects of assignment to active hormone therapy and baseline weight, older age (P 0.008) and higher physical activity level at baseline (P = 0.002) were also independently predictive of less weight gain. The impact of hormone therapy on weight gain was similar among subgroups, except for those defined by baseline smoking status (P = 0.04) and physical activity level at home (P = 0.02). Factors that were independently associated with smaller increases in girths were: for waist, greater overall activity (P = 0.005) and Hispanic ethnicity (P = 0.02); and for hip, work activity (P = 0.003) and greater alcohol consumption (P = 0.03). None of these factors significantly affected the observed overall relationships between estrogen and changes in girth.

Insulin lispro [Lys (B28), Pro (B29) human insulin] is a rapidly absorbed analog that has diminished tendency to self-associate. In four open-label, 1-year-long international randomized trials, we contrasted the immunogenicity of insulin lispro versus regular human insulin (RHI) in patients previously treated with insulin who had IDDM or NIDDM. Using a self-blank subtraction assay, we assessed sera for the presence of insulin-specific antibodies (ISA), insulin lispro-specific antibodies (LSA), and cross-reactive antibodies (CRA). Basal insulin needs were provided either with human ultralente (UL) or NPH insulins. After 2 to 4 weeks of therapy with RHI plus UL or RHI plus NPH, 50% of patients were randomly assigned to begin insulin lispro or continue on RHI. At baseline, few pretreated patients had LSA (0-4%) and approximately 10% had ISA, whereas 41-45% of patients with IDDM and 23-27% of patients with NIDDM had CRA (IDDM vs. NIDDM, P < 0.001). Within studies, no significant differences were noted over time in ISA, LSA, or CRA attributable to the type of short-acting insulin. When data were pooled, inconsistent changes were noted in ISA and LSA (LSA were greater in NIDDM vs. IDDM at baseline, P = 0.001, and ISA were greater in IDDM vs. NIDDM at 6 months, P = 0.007). Significant levels of CRA were more common in IDDM at all times (P < 0.001, P = 0.022, and P = 0.002 at baseline, 6 months, and 12 months, respectively). For patients receiving insulin lispro, no significant changes occurred in antibody status among IDDM and NIDDM patients throughout the study (became positive, remained positive, became negative, or remained negative). IDDM patients were more likely to develop or maintain CRA levels (P = 0.008 vs. NIDDM), whereas antibody levels were comparable among positive individuals. No evidence was noted that insulin lispro differs in immunogenicity from RHI in previously treated IDDM and NIDDM patients.

Severe ketotic diabetes induced in rats by streptozotocin resulted in a reduction in activity of the hepatic branched-chain alpha-ketoacid dehydrogenase complex, regardless of whether activity was expressed on the basis of liver wet weight, total liver, liver protein, or liver DNA. A decrease in enzyme specific activity (units of enzyme activity per mg of enzyme protein) was found responsible for the reduction in measurable enzyme activity of the complex. Insulin treatment reversed the decrease in enzyme specific activity. Treatment of tissue extracts with phosphoprotein phosphatase had no effect, indicating that activity of the complex was decreased by some mechanism other than reversible phosphorylation. Specific protein components of the complex were also not found reduced by the diabetic state. Induction of severe ketotic diabetes in rats previously fed a low-protein diet resulted in activation of the enzyme as a consequence of dephosphorylation. Nevertheless, the specific activity of the dephosphorylated enzyme of diabetic, low-protein-fed rats was decreased relative to that of control, low-protein-fed animals. Reconstitution studies with tissue extracts fortified with the purified E1 component indicate that severe diabetes induces a defect in this component of the hepatic branched-chain alpha-ketoacid dehydrogenase complex.

Objective: This study compared the performance of a new device that uses an IA to measure HbA1c in 9 min with a 1-microliter capillary blood sample with AC and CE methods in both nondiabetic and diabetic pediatric patients., Research Design and Methods: Two hundred seven pediatric subjects (103 nondiabetic, 104 with insulin-dependent diabetes mellitus) had HbA1c measured with the IA method and compared with total GHb values determined by AC and HbA1 by the CE method with the same whole-blood capillary aliquot. Glucose values were also obtained from the same blood samples., Results: Correlations and regression analyses show excellent correspondence between the three assays. The correlation between the AC and CE methods is 0.98 (P less than 0.001) with a slope of 1.615 +/- 0.0125 and intercept of 4.00 +/- 0.20. The correlation between the IA and AC methods is 0.99 (P less than 0.001) with a slope of 0.608 +/- 0.007 and intercept of 1.326 +/- 0.066. The correlation between the IA and CE methods is 0.97 (P less than 0.001), with a slope of 0.983 +/- 0.018 and intercept of 1.122 +/- 0.153. The average difference and average percentage difference between methods were also significant (P less than 0.001), reflecting the differences in GHb components measured. There was a significant correlation (P less than 0.001) between each method and glucose values (IA r = 0.72, AC r = 0.70, CE r = 0.73). Within-run precision for IA ranged from 1.7 to 3.5% and between-run precision 2.7 to 4.1%., Conclusions: Study results suggest that the IA method gives extremely accurate and reliable values over the clinical range of interest. The instrument is small, portable, easy to use, and provides information within 9 min for both physicians and patients.

Objective: We evaluated immunological and metabolic responses during therapy with beef (B), pork (P), human (H, rDNA), and sulfated beef (SB) insulins in patients with insulin-antibody-mediated insulin resistance., Research Design and Methods: A randomized double-blind sequential crossover study was performed with each insulin administered for 56 days unless dose reached 200 U/day or allergy developed. Participants were 26 individuals with history of B-P insulin dosage greater than or equal to 200 U/day and insulin binding capacities greater than 0.216 nM (30 mU/ml serum). Twenty-one participants completed the study. Insulin dosage/day, fasting plasma glucose, percentage HbA1, insulin antibody binding capacity (IABC), bound insulin (BI), percentage binding of 125I-labeled B, P, and H insulins, and receptor inhibition factor (RIF) were assessed., Results: Mean insulin dosage (U/day) was significantly greater on B (88.9) than on P (29.2), H (29.4), or SB (29.6). On B, dosage increased in 12 individuals and reached 200 U/day in 6 individuals. Mean fasting plasma glucose (12.1 mM) and HbA1 (11%) were significantly higher on B than on P, H, and SB. Mean IABC, bound insulin, RIF, and percentage of B, P, and H bound were significantly higher on B than on P, H, and SB. Prolonged treatment with SB before entry into the study (greater than 5 wk) resulted in a blunted anamnestic response to B insulin., Conclusions: Rechallenge with B results in anamnestic immunological response and deterioration of metabolic control. SB, H, and P insulins have equivalent effects in patients with insulin antibody-mediated immunologic resistance.

With an ultrasensitive noncompetitive enzyme-linked immunosorbent assay (ELISA), we tested the hypothesis that the presence of insulin autoantibodies in nondiabetic individuals is a normal event. Plasma and peripheral blood mononuclear cells were obtained from 50 nondiabetic whites for determination of insulin autoantibodies by ELISA and radioimmunoassay (anti-insulin IgG [AI-IgG] and 125I-labeled insulin bound [%]), islet cell antibodies, anti-nuclear antibodies and rheumatoid factor, and HLA class II-type antigens (DR, DRw, and DQ). The range of 125I-insulin binding was significantly less than was seen in pretreatment sera from individuals with diabetes (from -0.4 to 0.4% vs. -0.8 to 7.7%, respectively, P = 0.001). Eighty-eight percent of these nondiabetic individuals had significant levels of AI-IgG with preferential binding to human insulin. The geometric mean of AI-IgG concentrations in individuals with significant levels was 180 pM. Binding to human insulin was seen in 88%, to pork insulin in 42%, and to beef insulin in 24% of individuals (P less than 0.001 overall; P less than 0.05 where more bound to pork than beef insulin). Binding of AI-IgG to human insulin-coated plates was substantially inhibited by preincubation with human insulin (median inhibition 57.6%) with little if any inhibition by glucagon, C-peptide, albumin, or IgG. Four individuals had highly specific human AI-IgG as shown by immunoaffinity studies. AI-IgGs were significantly higher in individuals with the HLA haplotype DR4,DRw53,DQ3 and lower in individuals with DR5,DRw52,DQ1 (P = 0.03 for both).(ABSTRACT TRUNCATED AT 250 WORDS)

We compared glycosylated hemoglobin (GHb) determined from capillary blood samples on paper strips with a standard microcolumn technique in a cross-sectional observational study with laboratories blinded to duplicate samples. Both the standard and the filter strip laboratories were provided with 80 uniquely identified blood samples from 40 individuals. Each laboratory ran duplicate analyses on each sample, yielding 160 GHb values. The within-laboratory correlations between blinded duplicates were 0.98 for the standard (microcolumn technique) and 0.94 for the filter paper (affinity technique) laboratories. The between-laboratory correlations ranged from 0.69 to 0.77. When classifying patients by quartile of glycemic control, the laboratories agreed on 60% of the patients. In an effort to identify sources of between-laboratory variability, varying quantities of blood were applied to strips and reanalyzed. Five microliter drops always yielded inflated estimates of GHb. These data suggest that the estimates of GHb obtained from mail-in paper strips, although internally consistent, differ in important ways from standard laboratory values, reemphasizing the need for caution in the interpretation of interlaboratory and intermethod comparisons.

Our objective was to determine whether 1) hydrogenated starch hydrolysates (HSHs), bulking/sweetening agents used in hard candies, produce a diminished postmeal glycemic response relative to glucose in individuals with and without diabetes and 2) any diminished glycemia is secondary to altered carbohydrate absorption. This study followed a randomized double-blind crossover design and was performed in 12 individuals with diabetes (6 non-insulin dependent, 6 insulin dependent) and 6 nondiabetic individuals. Each group consisted of 3 men and 3 women, none with known neuropathy. After an overnight fast, each subject was challenged with 50 g of glucose, HSH 5875 (7% sorbitol/60% maltitol), and HSH 6075 (14% sorbitol/78% hydrogenated maltooligosaccharides)/1.73 m2 of body surface area in random order on 3 successive days. Individuals with diabetes were maintained on continuous subcutaneous insulin infusion throughout the study to achieve prechallenge glucose levels between 4.5 and 6.7 mM. For all groups, the order of plasma glucose responses over 5 h postchallenge was glucose greater than HSH 6075 greater than HSH 5875, P less than 0.001 (glucose vs. HSH). Pooled data for all groups for areas under the curve confirmed that HSH 6075 resulted in greater glycemia than HSH 5875 (P less than 0.05). This was reflected in the order of C-peptide responses seen in the nondiabetic and non-insulin-dependent groups (glucose greater than HSH 6075 greater than HSH 5875, P less than 0.001). Breath H2 after glucose was low, whereas HSH 5875 greater than HSH 6075 (P = 0.003). Gastric distress was noticed with all products.(ABSTRACT TRUNCATED AT 250 WORDS)

The immunogenicity of purified pork insulins (PPI) with and without (groups 1 and 2, respectively) trace contamination of beef insulin was contrasted with mixed beef pork insulin of lower purity (MBP, group 3) in 137 patients who had not previously been treated with insulin. Patients and physicians were blinded with regard to the species source of insulin and studies were conducted for a minimum of 1 yr. Antibody development to insulin was assessed by species-specific binding of 125I-insulin by acid charcoal extracted sera, as well as by measurement of insulin prebound to immunoglobulins by a polyethylene glycol precipitation method. NPH- and lente-treated individuals had equivalent antibody responses with regard to the rate of development of antibodies, and maximum immune responses to insulin. In all patient groups, antibody bound insulin as well as species-specific binding of 125I-insulin increased significantly over time (all P less than 0.01 for specific binding of pork and beef insulins SBP and SBB, as well as bound insulin). Maximum bound insulin and SBB as well as bound insulin and SBB over the entire course of the study were significantly greater in group 1 than in group 2 patients (both P less than 0.05). The rate of development and magnitude of antibodies' responses in both PPI-treated groups were significantly less than that seen in the MBP group (all P less than 0.01). New formation of antibeef proinsulin antibodies was seen in one patient from groups 1 and 3, but not in group 2. In all groups, insulin dose per day and fasting serum glucose concentrations increased by about 5 U/day and 10 mg/dl over 1 yr, but groups did not differ. MBP insulin used in these studies proved to be significantly less immunogenic than previously available Argentine pure beef insulin, purified by gel filtration. PPI containing even trace contamination of beef insulin was more immunogenic than PPI alone.

An 82-yr-old woman with type II diabetes developed antibody-mediated insulin resistance while on mixed pork-beef insulin concomitantly with a non-Hodgkin lymphoma. Insulin resistance was initially treated with highly purified pork insulin, but this was unsuccessful. Treatment with human insulin (recombinant DNA) was associated with marked decrease of both insulin requirement and high-affinity antibodies, increase of free insulin levels, and improvement of diabetic control. This patient's case shows that human insulin can be considered as an alternative treatment for immune-mediated insulin resistance.

Using doses of 0.1 and 0.15 U/kg, the hypoglycemic activities of neutral regular and NPH biosynthetic human insulin (BHI) and purified pork insulin were compared in normal fasting subjects. Neutral regular insulin was administered by the intravenous and subcutaneous routes and NPH subcutaneously. Comparison of the plasma glucose curves disclosed no statistically significant differences between the maximum effects and the length of time to achieve the maximum effect. Moreover, a dose-response difference between 0.1 and 0.15 U/kg could not established. It is concluded that the hypoglycemic activities of neutral regular and NPH BHI and purified pork insulin are the same.

Thirteen diabetic women were treated with human insulin of recombinant DNA origin from early pregnancy. One patient previously treated with conventional beef insulin showed a steady fall in insulin antibody levels whilst those previously treated with purified porcine insulin or human insulin showed no changes in species-specific insulin binding or in antibody-bound insulin. Two women with gestational diabetes, who received insulin for the first time during pregnancy, developed insulin antibodies which declined when therapy was withdrawn in the post-partum phase. Insulin antibody was detectable in the foetal circulation in all pregnancies at parturition but did not seem to be associated with any deleterious effect on carbohydrate metabolism in the neonate. Human insulin of recombinant DNA origin is a satisfactory treatment for diabetic pregnancy, is preferable to the use of conventional beef insulins in these patients and may confer a lesser risk of neonatal hypoglycaemia than purified pork insulin.

We studied the effects of exercise on the levels of plasma glucose and glucoregulatory hormones before and after 6 weeks of thrice-weekly physical training in 20 sedentary type II (non-insulin-dependent) diabetic patients and 11 control subjects matched for previous physical activity. Parameters were measured at rest, after 30 minutes of bicycle exercise at 70% to 75% of maximal oxygen uptake, and after 30 minutes of recovery. In the untrained state exercise resulted in a decrease in plasma glucose levels in diabetics but not in controls (-12 +/- 5 v + 4 +/- 2 mg/dL, P less than .01) and the expected drop in plasma insulin level was absent in diabetics. These differences in glucose and insulin response persisted after physical training. There was a tendency for patients with diabetes to have a smaller R-R interval variation during deep breathing, an abnormal resting heart rate response to physical training, and a lesser increment in plasma epinephrine levels following exercise, findings consistent with autonomic dysfunction. Physical training resulted in a blunting of the exercise-induced increment of plasma epinephrine, growth hormone, and lactate levels in control subjects, but not in diabetics. Our data demonstrate a hypoglycemic effect of exercise in mildly hyperglycemic nonobese type II diabetics. Possible causative factors include: hyperglycemia per se, a lack of physiologic suppression of plasma insulin, and abnormalities of autonomic or hypothalamic regulatory function.

To examine the effects of intensive patient and/or physician diabetes education on patient health outcomes, a controlled trial was conducted in which internal medicine residents and their 532 diabetic patients were randomly assigned to: routine care; patient education; physician education; or both patient and physician education. Patient outcome data were analyzed either by analysis of covariance on post intervention values (2-hour post-prandial plasma glucose [PPG]; body weight [BW]; blood pressure [BP]; or analysis of variance conducted on change values (fasting plasma glucose [FPG] and glycosylated hemoglobin [A1Hgb]). After patient education, significant improvements were observed in FPG, A1Hgb, BW, and systolic and diastolic BP. Physician education resulted in significant decreases in FPG, A1Hgb and BW. The combination of patient plus physician education resulted in the greatest improvements in patients' health outcomes including FPG, A1Hgb, PPG, BW and diastolic BP. Adjusted systolic BPs were not significantly different in the two groups. While these physiologic improvements were statistically and probably clinically significant, hyperglycemia and obesity still persisted. Thus, achieving optimal patient outcomes for a chronic disease like diabetes mellitus may require a greater or more effective use of resources than currently estimated.

A covalent aggregate twice the size of insulin accounts for approximately 28% of total circulating insulin immunoreactivity in type I diabetic patients. These aggregates are probably covalent dimers of insulin and should contain unique epitopes distinct from the parent molecule. Therapeutic insulin contains a similar material and is the source of the circulating aggregate. Anti-aggregate antibodies were detected by binding-inhibition techniques in 9 of 29 long-term diabetic patients. These antibodies were directed against structures distinct from those of the parent molecule insulin monomer. All antibody-positive patients were men whose blood also contained antibodies to insulin monomer. We conclude that the blood of approximately 30% of insulin-using diabetic patients contains antibodies directed against epitopes unique to the insulin aggregates. Because insulin monomer and aggregates probably share a common primary amino acid sequence, the anti-aggregate antibodies are probably directed against conformational determinants. Further work is needed to determine whether such aggregates promote or accentuate the development of anti-insulin antibodies in certain genetically predisposed individuals.

The Diabetes Education Study was a controlled trial of the effects of physician and patient education. This article describes an educational program for internal medicine residents and its effects on ambulatory diabetes management practices. Forty-five of 86 residents practicing in the general medicine clinic of a university-affiliated city/county hospital were assigned randomly to receive a multifaceted program intended to 1) provide specific care recommendations, 2) teach necessary skills, and 3) make the professional and institutional environment more supportive. During the subsequent 11 months, 323 diabetic patients were interviewed and their records audited for evidence of changes in care. Experimental residents utilized fasting blood glucose determinations more often than controls (i.e., during 40% of visits vs. 31%, p = 0.004). Experimental residents also engaged more frequently in a variety of recommended dietary management recommendations. Isolated differences in monitoring/management of chronic complications also were found (e.g., lipid screening: 70% of experimental residents' patients vs. 58%, p = 0.016). Intensive, multifaceted programs of this nature are concluded to result in improvements in diabetes care, over and above that which is attainable through routine methods of clinical training for residents.

We investigated the immunogenicity of human proinsulin (HPI) when used as the sole or principal insulin agonist in insulin-naive patients with insulin-dependent (type I) and non-insulin-dependent (type II) diabetes mellitus. Sixty-one patients (13 type I, 48 type II) were treated with rDNA human insulin (NPH HI with or without regular HI) and 53 were treated with HPI (8 type I, 45 type II). At 6 mo, virtually identical levels of HbA1c (5.2 vs. 5.3%, P = NS) were achieved. However, regular HI was added less often to the treatment regimen in HPI-treated patients (16 vs. 32 patients, P less than .001). Overall, there was no significant increase in proinsulin-specific antibodies in either treatment group. However, 8 of 51 (1 transiently) patients in the HPI group developed low levels of binding of HPI (highest percentage bound was 5%). Two patients in the HI group developed very low levels of HPI binding (1.2 and 1.9%). Binding of HI (greater than 2.4%) was seen in both treatment groups; however, the prevalence of HI binding was less in the HPI group at 6 mo (39 of 60 in HI group vs. 20 of 51 in HPI group, P = .008). Concomitant treatment with regular HI did not affect the prevalence or level of binding of HPI or HI. We conclude that human proinsulin is a weak immunogen when used as the principal insulin agonist and may reduce both the formation of anti-HI antibodies and the need for concomitant therapy with regular HI.

The prevalence of carotid artery occlusive disease (CAOD) in a population of adults with diabetes mellitus was determined, and factors associated with its presence were identified. By oculoplethysmography and phonoangiography, 20% of the population studied had detectable CAOD. Univariate analyses revealed that patients with CAOD had a higher prevalence of retinopathy proteinuria, a slower mean conduction velocity in two of three nerves tested, and more atherosclerosis in the leg arteries. Furthermore, increased age, higher cholesterol, lower fasting insulin, higher systolic blood pressure, and less adiposity were associated with the presence of CAOD. Sex, race, type of diabetes (type I or II), duration of diabetes, and measures of glycemia were not related to CAOD. When 10 variables were analyzed by multivariate methods, higher systolic blood pressure, higher cholesterol, and reduced adiposity were found to be the combination most significantly related to CAOD.

Androstenedione and testosterone labeled with 3H and 14C were fused simultaneously at constant rates into the brachial arm vein of 10 normal men. During the infusions blood samples were obtained from the brachial artery, a deep vein draining primarily muscle and a superficial vein draining primarily adipose tissue of the arm contra-lateral to the infusion. In the 10 men the mean +/- SE value for the fractional metabolism of adrostenedione by muscle is 0.20 +/- 0.30 which is not different from the mean value for the fractional metabolism by androstenedione by adipose tissue, 0.29 +/- 0.04. The mean value for the metabolism of testosterone by muscle, 0.04 +/- *.01, is significantly less than the metabolism by adipose tissue, *.11 +/- 0.01. Interconversion between adrostenedione and testosterone occurs in both tissues. The mean value for pA,T A,M is 0.024 + 0.005 and for pA,T A,AT is 0.024 +/- 0.005. The mean value for pT,A A,M is 0.005 +/- 0.003 and for pT,A A,AT is 0.008 +/- 0.003. The fractional metabolism of these androgens by these tissues is similar to the fractional metabolism of estrone and estradiol by these same tissues. Muscle appears to contribute about 5-12% of the overall metabolism of androstenedione and testosterone and 10-15% to theoverall conversion of androstenedione to testosterone. Adipose tissue contributes about 2-7% of the overall metabolism of these androgens and 5-10% of the overall conversion of androstenedione to testosterone, but less than 2% to the overall conversion of testosterone to androstenedione. In normal men, muscle appears to be more important to the metabolism of androstenedione and testosterone than is adipose tissue.