William T. Cefalu
American Diabetes Association
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Featured researches published by William T. Cefalu.
Diabetes | 2009
Zhanguo Gao; Jun Yin; Jin Jin Zhang; Robert E. Ward; Roy J. Martin; Michael Lefevre; William T. Cefalu; Jianping Ye
OBJECTIVE We examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a high-fat diet. RESEARCH DESIGN AND METHODS In dietary-obese C57BL/6J mice, sodium butyrate was administrated through diet supplementation at 5% wt/wt in the high-fat diet. Insulin sensitivity was examined with insulin tolerance testing and homeostasis model assessment for insulin resistance. Energy metabolism was monitored in a metabolic chamber. Mitochondrial function was investigated in brown adipocytes and skeletal muscle in the mice. RESULTS On the high-fat diet, supplementation of butyrate prevented development of insulin resistance and obesity in C57BL/6 mice. Fasting blood glucose, fasting insulin, and insulin tolerance were all preserved in the treated mice. Body fat content was maintained at 10% without a reduction in food intake. Adaptive thermogenesis and fatty acid oxidation were enhanced. An increase in mitochondrial function and biogenesis was observed in skeletal muscle and brown fat. The type I fiber was enriched in skeletal muscle. Peroxisome proliferator–activated receptor-γ coactivator-1α expression was elevated at mRNA and protein levels. AMP kinase and p38 activities were elevated. In the obese mice, supplementation of butyrate led to an increase in insulin sensitivity and a reduction in adiposity. CONCLUSIONS Dietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse. The mechanism of butyrate action is related to promotion of energy expenditure and induction of mitochondria function.
Diabetes Care | 2009
John B. Buse; Sonia Caprio; William T. Cefalu; Antonio Ceriello; Stefano Del Prato; Silvio E. Inzucchi; Sue McLaughlin; Gordon L. Phillips; R. Paul Robertson; Francesco Rubino; Richard Kahn; M. Sue Kirkman
The mission of the American Diabetes Association is “to prevent and cure diabetes and to improve the lives of all people affected by diabetes.” Increasingly, scientific and medical articles (1) and commentaries (2) about diabetes interventions use the terms “remission” and “cure” as possible outcomes. Several approved or experimental treatments for type 1 and type 2 diabetes (e.g., pancreas or islet transplants, immunomodulation, bariatric/metabolic surgery) are of curative intent or have been portrayed in the media as a possible cure. However, defining remission or cure of diabetes is not as straightforward as it may seem. Unlike “dichotomous” diseases such as many malignancies, diabetes is defined by hyperglycemia, which exists on a continuum and may be impacted over a short time frame by everyday treatment or events (medications, diet, activity, intercurrent illness). The distinction between successful treatment and cure is blurred in the case of diabetes. Presumably improved or normalized glycemia must be part of the definition of remission or cure. Glycemic measures below diagnostic cut points for diabetes can occur with ongoing medications (e.g., antihyperglycemic drugs, immunosuppressive medications after a transplant), major efforts at lifestyle change, a history of bariatric/metabolic surgery, or ongoing procedures (such as repeated replacements of endoluminal devices). Do we use the terms remission or cure for all patients with normal glycemic measures, regardless of how this is achieved? A consensus group comprised of experts in pediatric and adult endocrinology, diabetes education, transplantation, metabolism, bariatric/metabolic surgery, and (for another perspective) hematology-oncology met in June 2009 to discuss these issues. The group considered a wide variety of questions, including whether it is ever accurate to say that a chronic illness is cured; what the definitions of management, remission, or cure might be; whether goals of managing comorbid conditions revert to those of patients without diabetes if someone is …
The Lancet | 2013
William T. Cefalu; Lawrence A. Leiter; Kun-Ho Yoon; P. Arias; Leo Niskanen; John Xie; Dainius Balis; William Canovatchel; Gary Meininger
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of canagliflozin, an SGLT2 inhibitor, with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. METHODS We undertook this 52 week, randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28, 2009, and Dec 21, 2011. Patients aged 18-80 years with type 2 diabetes and glycated haemoglobin A1c (HbA1c) of 7·0-9·5% on stable metformin were randomly assigned (1:1:1) by computer-generated random sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily. Patients, study investigators, and local sponsor personnel were masked to treatment. The primary endpoint was change in HbA1c from baseline to week 52, with a non-inferiority margin of 0·3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, we assessed superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0·0%. Analysis was done in a modified intention-to-treat population, including all randomised patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00968812. FINDINGS 1450 of 1452 randomised patients received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference -0·01% [95% CI -0·11 to 0·09]), and canagliflozin 300 mg was superior to glimepiride (-0·12% [-0·22 to -0·02]). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 [11%] and 34 [14%] vs five [2%]; men: 17 [7%] and 20 [8%] vs three [1%]), urinary tract infections (31 [6%] for both canagliflozin doses vs 22 [5%]), and osmotic diuresis-related events (pollakiuria: 12 [3%] for both doses vs one [<1%]; polyuria: four [<1%] for both doses vs two [<1%]). INTERPRETATION Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving metformin. These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with metformin therapy. FUNDING Janssen Research & Development, LLC.
Diabetes, Obesity and Metabolism | 2010
Tina Vilsbøll; J. Rosenstock; Hannele Yki-Järvinen; William T. Cefalu; Y. Chen; E. Luo; B. Musser; Paula J. Andryuk; Y. Ling; Keith D. Kaufman; John M. Amatruda; Samuel S. Engel; L. Katz
Objective: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes.
Annals of Internal Medicine | 2001
William T. Cefalu; Jay S. Skyler; Ione A. Kourides; William H. Landschulz; Cecile C. Balagtas; Shu-Lin Cheng; Robert A. Gelfand
Subcutaneous insulin has been used to treat diabetes mellitus since the 1920s. Although insulin formulation has undergone numerous changes, the long-term benefit of glycemic control with intensive insulin therapy has only recently been demonstrated (1, 2). While conventional therapy relies on daily injections of prolonged-duration depot insulin, with or without reg-ular insulin, intensive insulin therapy relies heavily on frequent injections of regular insulin. Despite demonstrated benefits, intensive insulin therapy has not gained widespread clinical acceptance for several reasons (3-6): Multiple daily injections are inconvenient and adherence is a concern; the time-activity profile of regular insulin by injection poorly approximates the endogenous insulin secretory response to meals in a nondiabetic person; and successful implementation of an intensive regimen requires substantial time, effort, commitment, and communication for the patient and physician. These limitations may contribute to the high hemoglobin A1c levels observed in patients with type 2 diabetes. Alternate means of insulin delivery have been considered but have been met with limited success. Pulmonary delivery uses the bodys only highly permeable port of entry for macromolecules, the alveoli (3, 7-10). To capitalize on the advantages of pulmonary delivery, a dry powder insulin formula, along with an aerosol delivery system that permits noninvasive delivery of rapid-acting insulin, was developed. This study investigated the clinical utility and safety of inhaled insulin in patients with type 2 diabetes mellitus. Methods Patients Patients were 35 to 65 years of age, weighed 100% to 175% of ideal body weight (according to Metropolitan Life tables), were on a stable insulin schedule (two to three injections daily for 1 month), and had hemoglobin A1c levels of 0.07 to 0.12 (7.0% to 11.9%) and fasting C-peptide concentrations of 0.2 pmol/mL or greater. They also had normal results on chest radiography and pulmonary function tests. Exclusion criteria included a serum creatinine concentration of 265 mol/L (3.0 mg/dL) or greater; major organ system disease, except hypertension and complications directly related to diabetes (such as peripheral neuropathy, mild nephropathy, or retinopathy); smoking (active or within the past 6 months); current insulin pump therapy; injection regimen of four or more prescribed daily doses or more than 150 units of insulin daily; or concomitant oral antidiabetic therapy. Protocols were approved by the institutional review board of each participating center, and all patients gave written informed consent to participate in the study. Study Design During baseline, patients continued their usual two- to three-times-daily regimen of insulin therapy; were instructed on a weight-maintenance American Diabetes Association diet; performed home glucose monitoring; and underwent pulmonary function tests, assessment of glycemic indices, and a standardized meal study. At end of baseline, participants were hospitalized for 2 days and instructed in self-administration of inhaled insulin. Dry powder insulin was packaged in foil blister packs containing 1 mg or 3 mg of insulin. Each blisters contents were aerosolized using a wholly mechanical, hand-held inhaler (Inhale Therapeutic Systems, San Carlos, California) and delivered with a single inhalation. The mass median aerodynamic diameter of the aerosolized particles was approximately 3.5m making it suitable for alveolar deposition. Patients receiving inhaled insulin were given ultralente insulin (Humulin-U, Eli Lilly and Co., Indianapolis, Indiana) at bedtime as their sole long-acting insulin. Inhaled insulin was administered before each meal as one to two inhalations of the appropriate dose strength. Pharmacokinetic studies in healthy volunteers have demonstrated that each mg of inhaled insulin delivers to the circulation the rough equivalent of 3 units of subcutaneous insulin (Figure 1) (Unpublished data. Pfizer, Inc.). Thus, these pharmacokinetic studies suggest approximate starting doses of 3, 6, 9, 12, or 18 units. Dose titration was based on glucose response. Figure 1. Plasma insulin and plasma glucose responses to inhaled and injected insulin. squares triangles circles Top. Bottom. n Treatment Phase A blood glucose check (One Touch Profile, Lifescan, Milpitas, California) always preceded insulin administration. For each patient, glucose records were reviewed weekly. If mean preprandial glucose value since the patients last visit was outside the target range of 5.55 to 8.88 mmol/L (100 to 160 mg/dL), an adjusted insulin dose was recommended. Bedtime ultralente was adjusted weekly to achieve the same goal. Mild to moderate hypoglycemia was defined as typical symptoms without glucose measurement, symptoms plus a glucose level less than 3.33 mmol/L (<60 mg/dL), or any glucose level less than 2.8 mmol/L (<50 mg/dL). An episode was judged severe if it required assistance from another person or involved coma or seizure. Laboratory Tests Hemoglobin A1c was measured by using high-performance liquid chromatography (Biorad Diamat, Richmond, California); plasma glucose, by using a glucose oxidase method (Beckman Instruments, Palo Alto, California); insulin and C-peptide, by using double antibody radioimmunoassay. A central laboratory performed all laboratory tests (SmithKline Beecham, Philadelphia, Pennsylvania). Clinical Variables Pulmonary function tests were performed at baseline and at the end of the study by using methods certified by the American Thoracic Society. Specifically, tests were spirometry (to assess FVC, FEV1, and peak expiratory flow rate), lung volume (total lung capacity, functional residual capacity, residual volume), diffusion capacity, and oxygen saturation (by pulse oximetry). Meal studies occurred before and after the 12-week treatment phase to determine postprandial glycemic response. After an overnight fast, patients received Sustacal, 480 mL (Mead-Johnson, Nutritional Division, Evansville, Indiana), which was preceded by insulin administration. Specifically, at the baseline assessment, patients received subcutaneous insulin 30 minutes before the meal study, and at the end of the treatment phase, inhaled insulin was given 10 minutes before the meal study. Measurement of glucose levels was repeated at 2 hours after consumption. Statistical Analysis Efficacy was assessed by the 12-week change in hemoglobin A1c level from baseline. The 95% CI for the mean of the changes was calculated on the basis of the SE and the sampling t-distribution. Data are presented as the mean SD. Results Twenty-six participants (16 men, average body mass index of 30 kg/m2 [range, 23 to 37 kg/m2] and 10 women, average body mass index of 33 kg/m2 [range, 26 to 41 kg/m2]) were evaluated. The average age was 51.1 years (range, 39 to 64 years), and the average duration of diabetes was 11.2 years (range, 0.9 to 35 years). Inhaled insulin significantly improved glycemic control, as assessed by hemoglobin A1c level (Figure 2). Hemoglobin A1c level decreased from 0.0867 0.0144 (8.67% 1.44%) at baseline to 0.0796 0.0137 (7.96% 1.37%) by the end of the study (12-week change, 0.0071 0.0072 [0.71% 0.72%] [95% CI, 0.0010 to 0.0042 (1.00% to 0.42%)]). Figure 2. Change in mean hemoglobin A level during the 12-week treatment phase in type 2 diabetic patients receiving inhaled insulin therapy. Patients randomly assigned to receive inhaled insulin were given 14.6 5.1 mg of inhaled insulin and 35.7 18.4 U of ultralente insulin daily by the end of the study compared with 19 units of regular insulin and 51 units of long-acting insulin at baseline. Eighteen patients (69%) experienced mild to moderate hypoglycemic events, with an average of 0.83 episode per month. Patients had 39 hypoglycemic events in the first 4 weeks of the study and 22 events in the last 8 weeks. No severe events were recorded. Patients receiving inhaled insulin had no significant change from baseline (at which time they were receiving subcutaneous insulin before randomization) in postprandial glucose levels (13.3 3.1 mmol/L [240 56 mg/dL] at baseline vs. 13.4 3.2 mmol/L [241 57 mg/dL] by the end of the study) or in 2-hour glucose excursion (4.6 2.9 mmol/L at baseline [82 53 mg/dL] vs. 3.9 2.9 mmol/L [70 52 mg/dL] by the end of the study), and they showed no significant weight gain (12-week change, 0.3 2.9 kg). There were also no significant changes from baseline in spirometry results, lung volume, diffusion capacity, or oxygen saturation. Discussion We report on the efficacy of inhaled insulin in patients with type 2 diabetes who require insulin. Inhaled insulin improved glycemic control, was well tolerated, and demonstrated no adverse pulmonary effects. The therapeutic goal for diabetic patients is to achieve glucose levels as close to normal as possible, with a side effect profile that is acceptable to the patient and physician. Despite demonstrated benefits (1, 2), tight glucose control remains a largely unmet clinical challenge due, in part, to the shortcomings of the available subcutaneous methods. Limitations of multiple daily injections include inconvenience, poor patient acceptability and adherence, and the difficulty of matching postprandial insulin availability to postprandial requirement (3-6). The time-activity profile of subcutaneous regular insulin yields a slower onset and more prolonged duration than required. Consequently, insulin doses large enough to minimize early increases in postprandial glucose levels commonly predispose patients to later onset of hypoglycemia, whereas smaller doses, which avoid risk for hypoglycemia, provide inadequate control of peak postprandial glucose levels. Also, optimal timing of injections administered before meals may involve a delay before eating. Formulas with a more rapid onset are now available (11); however, the inconvenience of injections still exists. Development of oral, nasal, and t
Appetite | 2010
Stephen D. Anton; Corby K. Martin; Hongmei Han; Sandra Coulon; William T. Cefalu; Paula J. Geiselman; Donald A. Williamson
UNLABELLED Consumption of sugar-sweetened beverages may be one of the dietary causes of metabolic disorders, such as obesity. Therefore, substituting sugar with low calorie sweeteners may be an efficacious weight management strategy. We tested the effect of preloads containing stevia, aspartame, or sucrose on food intake, satiety, and postprandial glucose and insulin levels. DESIGN 19 healthy lean (BMI=20.0-24.9) and 12 obese (BMI=30.0-39.9) individuals 18-50 years old completed three separate food test days during which they received preloads containing stevia (290kcal), aspartame (290kcal), or sucrose (493kcal) before the lunch and dinner meal. The preload order was balanced, and food intake (kcal) was directly calculated. Hunger and satiety levels were reported before and after meals, and every hour throughout the afternoon. Participants provided blood samples immediately before and 20min after the lunch preload. Despite the caloric difference in preloads (290kcal vs. 493kcal), participants did not compensate by eating more at their lunch and dinner meals when they consumed stevia and aspartame versus sucrose in preloads (mean differences in food intake over entire day between sucrose and stevia=301kcal, p<.01; aspartame=330kcal, p<.01). Self-reported hunger and satiety levels did not differ by condition. Stevia preloads significantly reduced postprandial glucose levels compared to sucrose preloads (p<.01), and postprandial insulin levels compared to both aspartame and sucrose preloads (p<.05). When consuming stevia and aspartame preloads, participants did not compensate by eating more at either their lunch or dinner meal and reported similar levels of satiety compared to when they consumed the higher calorie sucrose preload.
Annals of Internal Medicine | 2005
Julio Rosenstock; Bernard Zinman; Liam J. Murphy; Stephen C. Clement; Paul Moore; C. Keith Bowering; Rosa Hendler; Shu-Ping Lan; William T. Cefalu
Context Because inhaled insulin acts very rapidly and lasts as long as regular insulin, mealtime dosing could control postmeal hyperglycemia. Content The authors randomly assigned 309 patients whose type 2 diabetes was poorly controlled with oral therapy to receive inhaled insulin at mealtime, either alone or with oral therapy, or to continue oral therapy. Compared with oral agent therapy alone, inhaled insulin combination therapy and monotherapy reduced hemoglobin A1c level by 1.67 percentage points and 1.18 percentage points, respectively. Patients receiving inhaled insulin gained more weight and had more episodes of hypoglycemia. Conclusions Inhaled insulin is effective in patients whose oral agent therapy has failed. Using it alone is surprisingly effective despite its short duration of action. The Editors The long-term benefits of good glycemic control are well-established for patients with type 1 and type 2 diabetes (1-9). In type 2 diabetes, the traditional treatment pathway generally involves the initiation of oral hypoglycemic agent therapy if lifestyle intervention is not effective (10). However, many patients will not achieve good glycemic control with oral agent therapy once insulin secretory capacity becomes insufficient (11). These patients must then receive insulin therapy to reduce the risk for diabetic complications. This usually involves the addition of basal insulin therapy to oral agents, although some studies suggest that insulin monotherapy is also effective (12-14). The optimal strategy for insulin add-on therapy is yet to be determined. Both patients and physicians are often reluctant to initiate subcutaneous insulin therapy (15-19). Consequently, the pulmonary route is being investigated as an alternative, less invasive method of insulin administration. Human inhaled insulin (Exubera; Pfizer Inc. [New York, New York], sanofi-aventis Group [Paris, France], and Nektar Therapeutics [San Carlos, California]) is a dry powder formulation and inhaler system currently in development (Figure 1). Figure 1. The inhaled insulin delivery system. Compared with injected regular insulin, inhaled insulin is more rapidly absorbed and eliminated and has a more rapid glucose-lowering effect (20). The pharmacodynamic profile of inhaled insulin has also been compared with the rapid-acting insulin analogue insulin lispro and regular human insulin at equivalent doses in healthy volunteers. Inhaled insulin had a faster onset of action than both insulin lispro and regular insulin, with a duration of action longer than insulin lispro and similar to regular insulin (21). These characteristics predict that inhaled insulin is suitable for administration before meals to control postprandial glycemia. In studies in patients with type 1 and type 2 diabetes, inhaled insulin has shown similar glycemic control to conventional subcutaneous regimens (22, 23). In addition, data from a small pilot study suggested that when oral agent therapy failed in patients with type 2 diabetes, adding premeal inhaled insulin to existing therapy significantly improved glycemic control (24). Our aim was to investigate whether monotherapy with inhaled insulin or therapy with inhaled insulin added to dual oral agent therapy can improve glycemic control in patients with type 2 diabetes, compared with those continuing a stable regimen of dual oral agent therapy. We also assessed the tolerability and safety of inhaled insulin therapy over a 3-month period. Methods Participants We screened male and female outpatients 35 to 80 years of age who had received a diagnosis of type 2 diabetes mellitus, as defined by the American Diabetes Association (ADA) (25), at least 1 year earlier at 48 centers in the United States and Canada. Patients were already attending the investigators clinic or were recruited by physician referral. For 2 months before the baseline lead-in period, patients were required to have been treated with a stable oral agent regimen involving 2 antidiabetic medications: 1 insulin secretagogue (a sulfonylurea or repaglinide) and 1 insulin sensitizer (a thiazolidinedione or metformin). In addition, patients were required to have a hemoglobin A1c level of 8% or greater at screening (week 4) and prerandomization (week 1) for eligibility. Exclusion criteria included hemoglobin A1c level greater than 11%; body mass index greater than 35 kg/m2; poorly controlled asthma; clinically significant chronic obstructive pulmonary disease or other clinically significant respiratory disease; smoking during the previous 6 months; abnormal pulmonary function at screening (carbon monoxide diffusing capacity < 75%, total lung capacity < 80% or > 120%, and FEV1 < 70% of predicted); clinically significant major organ system disease; abnormal electrocardiogram; abnormalities on laboratory screening; systemic glucocorticoid therapy; known drug or alcohol dependence; previous inhaled insulin use; or pregnancy, lactation, or planned pregnancy. We also excluded patients with a predisposition to severe hypoglycemia (2 severe episodes within the past 6 months) or any hospitalization or emergency department visit due to poor diabetic control within the past 6 months. Study Design This was an open-label, 12-week, parallel-group, multicenter, randomized study. The independent local institutional review boards of all participating centers approved the protocol. All patients provided written informed consent. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki. Using a computer-generated randomization scheme, we randomly assigned eligible patients to receive premeal inhaled insulin (Exubera) plus their existing stable regimen of 2 oral agents (n= 102) (inhaled insulin plus 2 oral agents group), to receive a premeal inhaled insulin regimen (n= 105) (inhaled insulin monotherapy group), or to be in the comparator group and continue receiving their existing stable regimen of dual oral agent therapy (n= 102) (2 oral agents group). Randomization was not within center. A system of interactive voice-response technology assigned the randomization codes. The investigator dialed a central database, where the master randomization list was held, and answered a series of prompts (for example, protocol number and center identification), which determined the specific treatment group assignment. At screening, 90%, 87%, and 90% of patients in the inhaled insulin plus 2 oral agents, inhaled insulin monotherapy, and 2 oral agents groups, respectively, were using metformin (mean dosage, approximately 2100 mg/d). Furthermore, 58%, 65%, and 63% of patients, respectively, were using glyburide (mean dosage, approximately 19 mg/d), and 27%, 23%, and 26% of patients, respectively, were using glipizide (mean dosage, approximately 20 mg/d). Five patients in the inhaled insulin plus 2 oral agents group, 3 patients in the inhaled insulin monotherapy group, and 4 patients in the 2 oral agents group were using troglitazone (400 mg to 600 mg). Since troglitazone was withdrawn from the market while the study was in progress, we required patients who were receiving troglitazone (n= 4) to switch to another thiazolidinedione. We recommended that patients who were receiving 400 mg or 600 mg of troglitazone switch to 4 mg of rosiglitazone or 30 mg of pioglitazone or to 8 mg of rosiglitazone or 45 mg of pioglitazone, respectively. Patients who switched from troglitazone therapy could continue participation in the study with no delay in study procedure schedules. Patients received dietary instruction in accordance with ADA recommendations (26). We also instructed patients to perform 30 minutes of moderate exercise at least 3 days per week, per ADA guidelines (27). Inhaled insulin was administered within 10 minutes before meals. Before beginning the study, we trained patients in the appropriate procedure for inhalation of insulin. The insulin was available in 1-mg and 3-mg blister packs (1 mg is equivalent to approximately 2.5 U to 3.0 U of subcutaneously injected insulin). Typically, patients administered 1 or 2 inhalations for any given dose. We based initial recommended doses for inhaled insulin on factors such as the patients weight and degree of glycemic control (Appendix 1). The doses of the oral agents were kept stable for the duration of the study. We instructed patients to self-monitor blood glucose levels by using the Accu-Chek Complete glucometer (Roche Diagnostics, Basel, Switzerland) and to assess their blood glucose levels at least 4 times daily (before breakfast, lunch, and supper and at bedtime) with results recorded on a worksheet. Glycemic targets were 4.4 to 7.8 mmol/L (80 to 140 mg/dL) before breakfast, lunch, and supper and 5.6 to 8.9 mmol/L (100 to 160 mg/dL) at bedtime. Patients measured their blood glucose levels before administering insulin. We based recommended doses for prebreakfast, prelunch, and presupper inhaled insulin on review of the mean results for the prelunch, presupper, and bedtime self-monitored blood glucose levels, respectively, between clinic visits (Appendix 1). Doses of inhaled insulin could be altered according to guidelines in case the glucose concentrations were outside these ranges, in anticipation of a smaller or larger meal, or on an as-needed basis. Assessments The primary efficacy end point was the change in hemoglobin A1c level from baseline to week 12. We measured hemoglobin A1c at screening and at weeks 1, 0, 6, and 12. We defined baseline hemoglobin A1c as the average of the week 1 and week 0 values (if either value was missing, baseline was the nonmissing value). Secondary efficacy end points included changes in fasting plasma glucose level and 2-hour postprandial glucose concentration and percentage of patients achieving acceptable (hemoglobin A1c level < 8.0%) or good (hemoglobin A1c level < 7.0%) glycemic control at the end of the study. We measured fasting plasma glucose levels at weeks 4, 1, 0, and 12 i
Journal of Clinical Investigation | 2012
J. Scott Gabrielsen; Yan Gao; Judith A. Simcox; Jingyu Huang; David Thorup; Deborah Jones; Robert C. Cooksey; David Gabrielsen; Ted D. Adams; Steven C. Hunt; Paul N. Hopkins; William T. Cefalu; Donald A. McClain
Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores.
Metabolism-clinical and Experimental | 2008
Barbara Schmidt; David M. Ribnicky; Alexander Poulev; Sithes Logendra; William T. Cefalu; Ilya Raskin
Plants have been used as a source of medicine throughout history and continue to serve as the basis for many pharmaceuticals used today. Although the modern pharmaceutical industry was born from botanical medicine, synthetic approaches to drug discovery have become standard. However, this modern approach has led to a decline in new drug development in recent years and a growing market for botanical therapeutics that are currently available as dietary supplements, drugs, or botanical drugs. Most botanical therapeutics are derived from medicinal plants that have been cultivated for increased yields of bioactive components. The phytochemical composition of many plants has changed over time, with domestication of agricultural crops resulting in the enhanced content of some bioactive compounds and diminished content of others. Plants continue to serve as a valuable source of therapeutic compounds because of their vast biosynthetic capacity. A primary advantage of botanicals is their complex composition consisting of collections of related compounds having multiple activities that interact for a greater total activity.
Experimental Biology and Medicine | 2001
William T. Cefalu
Insulin resistance is defined as a clinical state in which a normal or elevated insulin level produces an attenuated biologic response. Specifically, the biologic response most studied is insulin-stimulated glucose disposal, yet the precise cellular mechanism responsible is not yet known. However, the presence of insulin resistance is observed many years before the onset of clinical hyperglycemia and the diagnosis of Type 2 diabetes. Insulin resistance at this stage appears to be significantly associated with a clustering of cardiovascular risk factors predisposing the individual to accelerated cardiovascular disease. An overview of insulin resistance and the associated clinical insulin resistant state will be discussed.