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1.  Effects of High-Protein Versus High-Carbohydrate Diets on Markers of β-Cell Function, Oxidative Stress, Lipid Peroxidation, Proinflammatory Cytokines, and Adipokines in Obese, Premenopausal Women Without Diabetes 
Diabetes Care  2013;36(7):1919-1925.
To study the effects of high-protein versus high-carbohydrate diets on various metabolic end points (glucoregulation, oxidative stress [dichlorofluorescein], lipid peroxidation [malondialdehyde], proinflammatory cytokines [tumor necrosis factor-α and interleukin-6], adipokines, and resting energy expenditure [REE]) with high protein–low carbohydrate (HP) and high carbohydrate–low protein (HC) diets at baseline and after 6 months of dietary intervention.
We recruited obese, premenopausal women aged 20–50 years with no diabetes or prediabetes who were randomized to HC (55% carbohydrates, 30% fat, and 15% protein) or HP (40% carbohydrates, 30% fat, and 30% protein) diets for 6 months. The diets were provided in prepackaged food, which provided 500 kcal restrictions per day. The above metabolic end points were measured with HP and HC diet at baseline and after 6 months of dietary intervention.
After 6 months of the HP versus HC diet (12 in each group), the following changes were significantly different by Wilcoxon rank sum test for the following parameters: dichlorofluorescein (−0.8 vs. −0.3 µmol/L, P < 0.0001), malondialdehyde (−0.4 vs. −0.2 μmol/L, P = 0.0004), C-reactive protein (−2.1 vs. −0.8 mg/L, P = 0.0003), E-selectin (−8.6 vs. −3.7 ng/mL, P = 0.0007), adiponectin (1,284 vs. 504 ng/mL, P = 0.0011), tumor necrosis factor-α (−1.8 vs. −0.9 pg/mL, P < 0.0001), IL-6 (−1.3 vs. −0.4 pg/mL, P < 0.0001), free fatty acid (−0.12 vs. 0.16 mmol/L, P = 0.0002), REE (259 vs. 26 kcal, P < 0.0001), insulin sensitivity (4 vs. 0.9, P < 0.0001), and β-cell function (7.4 vs. 2.1, P < 0.0001).
To our knowledge, this is the first report on the significant advantages of a 6-month hypocaloric HP diet versus hypocaloric HC diet on markers of β-cell function, oxidative stress, lipid peroxidation, proinflammatory cytokines, and adipokines in normal, obese females without diabetes.
PMCID: PMC3687312  PMID: 23404297
2.  Acidosis: The Prime Determinant of Depressed Sensorium in Diabetic Ketoacidosis 
Diabetes Care  2010;33(8):1837-1839.
The etiology of altered sensorium in diabetic ketoacidosis (DKA) remains unclear. Therefore, we sought to determine the origin of depressed consciousness in DKA.
We analyzed retrospectively clinical and biochemical data of DKA patients admitted in a community teaching hospital.
We recorded 216 cases, 21% of which occurred in subjects with type 2 diabetes. Mean serum osmolality and pH were 304 ± 31.6 mOsm/kg and 7.14 ± 0.15, respectively. Acidosis emerged as the prime determinant of altered sensorium, but hyperosmolarity played a synergistic role in patients with severe acidosis to precipitate depressed sensorium (odds ratio 2.87). Combination of severe acidosis and hyperosmolarity predicted altered consciousness with 61% sensitivity and 87% specificity. Mortality occurred in 0.9% of the cases.
Acidosis was independently associated with altered sensorium, but hyperosmolarity and serum “ketone” levels were not. Combination of hyperosmolarity and acidosis predicted altered sensorium with good sensitivity and specificity.
PMCID: PMC2909073  PMID: 20484127
3.  Hyperglycemic Crises in Adult Patients With Diabetes 
Diabetes Care  2009;32(7):1335-1343.
PMCID: PMC2699725  PMID: 19564476
4.  Is a Priming Dose of Insulin Necessary in a Low-Dose Insulin Protocol for the Treatment of Diabetic Ketoacidosis?  
Diabetes Care  2008;31(11):2081-2085.
OBJECTIVE—The purpose of this study was to assess the efficacy of an insulin priming dose with a continuous insulin infusion versus two continuous infusions without a priming dose.
RESEARCH DESIGN AND METHODS—This prospective randomized protocol used three insulin therapy methods: 1) load group using a priming dose of 0.07 units of regular insulin per kg body weight followed by a dose of 0.07 unit · kg−1 · h−1 i.v. in 12 patients with diabetic ketoacidosis (DKA); 2) no load group using an infusion of regular insulin of 0.07 unit · kg body weight−1 · h−1 without a loading dose in 12 patients with DKA, and 3) twice no load group using an infusion of regular insulin of 0.14 · kg−1 · h−1 without a loading dose in 13 patients with DKA. Outcome was based on the effects of insulin therapy on biochemical and hormonal changes during treatment and recovery of DKA.
RESULTS—The load group reached a peak in free insulin value (460 μU/ml) within 5 min and plateaued at 88 μU/ml in 60 min. The twice no load group reached a peak (200 μU/ml) at 45 min. The no load group reached a peak (60 μU/ml) in 60–120 min. Five patients in the no load group required supplemental insulin doses to decrease initial glucose levels by 10%; patients in the twice no load and load groups did not. Except for these differences, times to reach glucose ≤250 mg/dl, pH ≥7.3, and HCO3− ≥15 mEq/l did not differ significantly among the three groups.
CONCLUSIONS—A priming dose in low-dose insulin therapy in patients with DKA is unnecessary if an adequate dose of regular insulin of 0.14 unit · kg body weight−1 · h−1 (about 10 units/h in a 70-kg patient) is given.
PMCID: PMC2571050  PMID: 18694978
5.  Evaluation of early weight loss thresholds for identifying non-responders to an intensive lifestyle intervention 
Obesity (Silver Spring, Md.)  2014;22(7):1608-1616.
Weight losses in lifestyle interventions are variable, yet prediction of long-term success is difficult.
We examined the utility of using various weight loss thresholds in the first 2 months of treatment for predicting 1-year outcomes.
Design and Methods
Participants included 2327 adults with type 2 diabetes (BMI:35.8±6.0) randomized to the intensive lifestyle intervention (ILI) of the Look AHEAD trial. ILI included weekly behavioral sessions designed to increase physical activity and reduce caloric intake. 1-month, 2-month, and 1-year weight changes were calculated.
Participants failing to achieve a ≥2% weight loss at Month 1 were 5.6 (95% CI:4.5,7.0) times more likely to also not achieve a ≥10% weight loss at Year 1, compared to those losing ≥2% initially. These odds were increased to 11.6 (95% CI:8.6,15.6) when using a 3% weight loss threshold at Month 2. Only 15.2% and 8.2% of individuals failing to achieve the ≥2% and ≥3% thresholds at Months 1 and 2 respectively, go on to achieve a ≥10% weight loss at Year 1.
Given the association between initial and 1-year weight loss, the first few months of treatment may be an opportune time to identify those who are unsuccessful and utilize rescue efforts.
PMCID: PMC4077939  PMID: 24771618
weight loss; behavioral treatment; lifestyle intervention
6.  Intensive Lifestyle Intervention Reduces Urinary Incontinence in Overweight/Obese Men with Type 2 Diabetes: Results from the Look AHEAD Trial 
The Journal of urology  2014;192(1):144-149.
We determined the effect of an intensive lifestyle intervention on the prevalence, incidence and resolution of bothersome nocturia, increased daytime urinary voiding and urinary incontinence in overweight/obese men with type 2 diabetes after 1 year in the Look AHEAD trial.
Materials and Methods
A subset of male Look AHEAD participants was selected for this secondary data analysis. Overall 1,910 men with an average (mean ± SD) age of 59.9 ± 6.7 years and body mass index of 35.2 ± 5.5 kg/m2 were randomized to an intensive lifestyle intervention or diabetes support and education group. All participants self-reported information regarding incontinence, nocturia and daytime urinary voiding at entry and 1 year.
After 1 year the intensive lifestyle intervention group lost significantly more weight than the diabetes support and education group (9.4% ± 7.0% vs 0.7% ± 4.5%, respectively; p <0.001). The odds of prevalent urinary incontinence at 1 year were reduced by 38% in the intensive lifestyle intervention group compared to the diabetes support and education group. The prevalence of urinary incontinence decreased from 11.3% to 9.0% in the intensive lifestyle intervention group and increased from 9.7% to 11.6% in the diabetes support and education group. The intensive lifestyle intervention group also had increased odds of urinary incontinence resolving (OR 1.93, 95% CI 1.04–3.59, p = 0.04 and 56.0% vs 40.7%, p = 0.03) and trend toward reduced odds of new onset, incident urinary incontinence (OR 0.66, 95% CI 0.42–1.02, p = 0.06) compared with the diabetes support and education arm. In contrast, no differences between intensive lifestyle intervention and diabetes support and education were seen at 1 year for frequency of nocturia or frequency of daytime voiding.
Intensive lifestyle intervention should be considered for the treatment of urinary incontinence in overweight/obese men with type 2 diabetes.
PMCID: PMC4133305  PMID: 24533998
diabetes mellitus; weight loss; urinary incontinence; nocturia
7.  Human Cardiovascular Disease IBC Chip-Wide Association with Weight Loss and Weight Regain in the Look AHEAD Trial 
Human heredity  2013;75(0):160-174.
The present study identified genetic predictors of weight change during behavioral weight loss treatment.
Participants were 3,899 overweight/obese individuals with type 2 diabetes from Look AHEAD, a randomized controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Analyses focused on associations of single nucleotide polymorphisms (SNPs) on the Illumina CARe iSelect (IBC) chip (minor allele frequency >5%; n = 31,959) with weight change at year 1 and year 4, and weight regain at year 4, among individuals who lost ≥ 3% at year 1.
Two novel regions of significant chip-wide association with year-1 weight loss in ILI were identified (p < 2.96E-06). ABCB11 rs484066 was associated with 1.16 kg higher weight per minor allele at year 1, whereas TNFRSF11A, or RANK, rs17069904 was associated with 1.70 kg lower weight per allele at year 1.
This study, the largest to date on genetic predictors of weight loss and regain, indicates that SNPs within ABCB11, related to bile salt transfer, and TNFRSF11A, implicated in adipose tissue physiology, predict the magnitude of weight loss during behavioral intervention. These results provide new insights into potential biological mechanisms and may ultimately inform weight loss treatment.
PMCID: PMC4257841  PMID: 24081232
Type 2 diabetes; Obesity; Weight loss; Diet; Genetics
9.  Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk 
Diabetes Care  2013;36(11):3607-3612.
Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance.
We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.
In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ∆G0–120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ∆I0–120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [∆I0–120/∆G0–120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.
In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).
PMCID: PMC3816921  PMID: 24062330
10.  Prevention of Diabetes With Pioglitazone in ACT NOW 
Diabetes  2013;62(11):3920-3926.
We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.
PMCID: PMC3806596  PMID: 23863810
11.  Effect of Intensive Lifestyle Intervention on Sexual Dysfunction in Women With Type 2 Diabetes 
Diabetes Care  2013;36(10):2937-2944.
Sexual dysfunction is a prevalent problem in obese women with type 2 diabetes. This study examined the effects of intensive lifestyle intervention (ILI) in these women.
Look AHEAD is a 16-center, randomized, controlled trial evaluating the health effects of ILI compared with a control group (diabetes support and education [DSE]). The Look AHEAD Sexual Function Ancillary study included 375 female participants at five Look AHEAD sites. Participants completed the Female Sexual Function Inventory (FSFI) and Beck Depression Inventory (BDI), and assessments of weight and cardiovascular risk factors at baseline and 1 year were made.
At baseline, 50% of the 229 participants who reported being sexually active met criteria for female sexual dysfunction (FSD); only BDI score was related to FSD. One-year weight losses were greater in the ILI group than in the DSE group (7.6 vs. 0.45 kg; P < 0.001). Among women with FSD at baseline, those in the ILI group (N = 60) compared with those in the DSE group (N = 53) were significantly more likely to remain sexually active (83 vs. 64%; P < 0.008), reported greater improvement in total FSFI scores and in most FSFI domains (P < 0.05), and were more likely to experience remission of FSD (28 vs. 11%; P < 0.04) at 1 year. No significant differences between ILI and DSE were seen in women who did not have FSD at baseline.
Participation in ILI appeared to have beneficial effects on sexual functioning among obese women with diabetes, particularly in those who had FSD at baseline.
PMCID: PMC3781524  PMID: 23757437
12.  Do Genetic Modifiers of HDL-C and Triglyceride Levels also Modify Their Response to a Lifestyle Intervention in the Setting of Obesity and Type-2 Diabetes Mellitus? The Look AHEAD Study 
High-density lipoprotein cholesterol (HDL-C) and triglycerides are cardiovascular risk factors susceptible to lifestyle behavior modification and genetics. We hypothesized that genetic variants identified by genome-wide association studies (GWASs) as associated with HDL-C or triglyceride levels will modify 1-year treatment response to an intensive lifestyle intervention (ILI), relative to a usual care of diabetes support and education (DSE).
Methods and Results
We evaluated 82 SNPs, representing 31 loci demonstrated by GWAS to be associated with HDL-C and/or triglycerides, in 3,561 participants who consented for genetic studies and met eligibility criteria. Variants associated with higher baseline HDL-C levels, cholesterol ester transfer protein (CETP) rs3764261 and hepatic lipase (LIPC) rs8034802, were found to be associated with HDL-C increases with ILI (p=0.0038 and 0.013, respectively) and had nominally significant treatment interactions (p=0.047 and 0.046, respectively). The fatty acid desaturase-2 (FADS-2) rs1535 variant, associated with low baseline HDL-C (p=0.017), was associated with HDL-C increases with ILI (0.0037) and had a nominal treatment interaction (p= 0.035). ApoB (rs693) and LIPC (rs8034802) SNPs showed nominally significant associations with HDL-C and triglyceride changes with ILI and a treatment interaction (p<0.05). A PGS1 SNP (rs4082919) showed the most significant triglyceride treatment interaction in the full cohort (p=0.0009).
This is the first study to identify genetic variants modifying lipid responses to a randomized lifestyle behavior intervention in overweight/obese diabetic individuals. The effect of genetic factors on lipid changes may differ from the effects on baseline lipids and are modifiable by behavioral intervention.
PMCID: PMC4077278  PMID: 23861364
genomics; physiological; cholesterylester transfer protein genetics; triglycerides; behavior modification; lipoprotein
13.  FTO predicts weight regain in the Look AHEAD Clinical Trial 
International journal of obesity (2005)  2013;37(12):10.1038/ijo.2013.54.
Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss.
Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3,899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and Diabetes Support and Education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity-risk polymorphisms in 8 genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1.
No SNPs were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, FTO rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, p = 0.005), but not ILI (p = 0.761), resulting in SNP×treatment arm interaction (p = 0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (p=0.051).
Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.
PMCID: PMC3750057  PMID: 23628854
type 2 diabetes; obesity; weight loss, diet, genetics
14.  The long-term effectiveness of a lifestyle intervention in severely obese individuals 
The American journal of medicine  2013;126(3):236-242.e2.
Severe obesity (BMI≥40kg/m2) is a serious public health concern. Although bariatric surgery is an efficacious treatment approach, it is limited in reach; thus non-surgical treatment alternatives are needed. We examined the 4-year effects of an intensive lifestyle intervention on body weight and cardiovascular disease risk factors among severely obese, compared to overweight (25≤BMI<30), class I (30≤BMI<35), and class II obese (35≤BMI<40) participants.
5,145 individuals with type 2 diabetes (45–76 years, BMI≥25kg/m2) were randomized to an intensive lifestyle intervention or diabetes support and education. The lifestyle intervention received a behavioral weight loss program which included group and individuals meetings, a ≥10% weight loss goal, calorie restriction, and increased physical activity. Diabetes support and education received a less intense educational intervention. 4-year changes in body weight and cardiovascular disease risk factors were assessed.
Across BMI categories, 4-year changes in body weight were significantly greater in lifestyle participants compared to diabetes support and education (p’s<0.05). At year 4, severely obese lifestyle participants lost 4.9±8.5% which was similar to class I (4.8±7.2%) and class II obese (4.4±7.6%) and significantly greater than overweight (3.4±7.0%; p<0.05). 4-year changes in LDL-cholesterol, triglycerides, diastolic blood pressure, HbA1c, and blood glucose were similar across BMI categories in lifestyle participants; however the severely obese had less favorable improvements in HDL-cholesterol (3.1±0.4mg/dL) and systolic blood pressure (−1.4±0.7mmHg) compared to the less obese (p’s<0.05).
Lifestyle interventions can result in important long-term weight losses and improvements in cardiovascular disease risk factors among a significant proportion of severely obese individuals.
PMCID: PMC3574274  PMID: 23410564
Severe obesity; weight loss; lifestyle intervention; diabetes; cardiovascular disease
15.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
16.  Patterns of Weight Change Associated with Long-Term Weight Change and Cardiovascular Disease Risk Factors in the Look AHEAD Study 
Obesity (Silver Spring, Md.)  2012;20(10):2048-2056.
This paper provides an assessment of the associations that weight loss patterns during the first year of an intensive lifestyle intervention have with four year maintenance and health outcomes. Two components described patterns of weight change during the first year of intervention: one reflected the typical pattern of weight loss over the 12 months, but distinguished those who lost larger amounts across the monthly intervals from those who lost less. The second component reflected the weight change trajectory, and distinguished a pattern of initial weight loss followed by regain versus a more sustained pattern of weight loss 2,438 individuals aged 45–76 years with type 2 diabetes mellitus, who enrolled in the weight loss intervention of a randomized clinical trial, were assigned scores according to how their weight losses reflected these patterns. Relationships these scores had with weight losses and health outcomes (glycosolated hemoglobin – HbA1c; systolic blood pressure, HDL-cholesterol, and triglycerides) over four years were described. Both individuals who had larger month-to-month weight losses in year 1 and whose weight loss was more sustained during the first year had better maintenance of weight loss over four years, independent of characteristics traditionally linked to weight loss success (p<0.001). While relationships with year 4 weight loss were stronger, the pattern of larger monthly weight loss during year 1 was also independently predictive of year 4 levels of HbA1c, HDL-cholesterol, and systolic blood pressure.
PMCID: PMC3632374  PMID: 22327053
weight loss; type 2 diabetes mellitus; principal components analysis
17.  Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes 
The prevalence of type 2 diabetes continues to increase at an alarming rate around the world, with even more people being affected by prediabetes. Although the pathogenesis and long-term complications of type 2 diabetes are fairly well known, its treatment has remained challenging, with only half of the patients achieving the recommended hemoglobin A1c target. This narrative review explores the pathogenetic rationale for the treatment of type 2 diabetes, with the view of fostering better understanding of the evolving treatment modalities. The diagnostic criteria including the role of hemoglobin A1c in the diagnosis of diabetes are discussed. Due attention is given to the different therapeutic maneuvers and their utility in the management of the diabetic patient. The evidence supporting the role of exercise, medical nutrition therapy, glucose monitoring, and antiobesity measures including pharmacotherapy and bariatric surgery is discussed. The controversial subject of optimum glycemic control in hospitalized and ambulatory patients is discussed in detail. An update of the available pharmacologic options for the management of type 2 diabetes is provided with particular emphasis on newer and emerging modalities. Special attention has been given to the initiation of insulin therapy in patients with type 2 diabetes, with explanation of the pathophysiologic basis for insulin therapy in the ambulatory diabetic patient. A review of the evidence supporting the efficacy of the different preventive measures is also provided.
PMCID: PMC3746516  PMID: 21134520
18.  A Comparison Study of Continuous Insulin Infusion Protocols in the Medical Intensive Care Unit: Computer-Guided Vs. Standard Column-Based Algorithms 
To compare the safety and efficacy of continuous insulin infusion (CII) via a computer-guided and a standard paper form protocol in a medical intensive care unit (ICU).
Multicenter randomized trial of 153 ICU patients randomized to CII using the Glucommander (n = 77) or a standard paper protocol (n = 76). Both protocols used glulisine insulin and targeted blood glucose (BG) between 80 mg/dL and 120 mg/dL.
The Glucommander resulted in a lower mean BG value (103 ± 8.8 mg/dL vs. 117 ± 16.5 mg/dL, P < 0.001) and in a shorter time to reach BG target (4.8 ± 2.8 vs.7.8 hours ± 9.1 hours, P < 0.01), and once at target resulted in a higher percentage of BG readings within target (71.0 ± 17.0% vs. 51.3 ± 19.7%, P < 0.001) than the standard protocol. Mean insulin infusion rate in the Glucommander was similar to the standard protocol (P = 0.12). The percentages of patients with ≥1 episode of BG <40 mg/dL and <60 mg/dL were 3.9% and 42.9% in the Glucommander and 5.6% and 31.9% in the standard, respectively [P = not significant (NS)]. Repeated measures analyses show that the probabilities of BG reading <40 mg/dL or <60 mg/dL were not significantly different between groups (P = 0.969, P = 0.084) after accounting for within-patient correlations with or without adjusting for time effect. There were no differences between groups in the length of hospital stay (P = 0.704), ICU stay (P = 0.145), or inhospital mortality (P = 0.561).
Both treatment algorithms resulted in significant improvement in glycemic control in critically ill patients in the medical ICU. The computer-based algorithm resulted in tighter glycemic control without an increased risk of hypoglycemic events compared to the standard paper protocol.
PMCID: PMC3733454  PMID: 20945468
diabetes; hospital; hyperglycemia; hypoglycemia; insulin infusion; intensive care unit
19.  Menopause and risk of diabetes in the Diabetes Prevention Program 
Menopause (New York, N.Y.)  2011;18(8):857-868.
The study objective was to examine the association between menopause status and diabetes risk among women with glucose intolerance and to determine if menopausal status modifies response to diabetes prevention interventions.
The study population included women in premenopause (n=708), natural postmenopause (n=328), and bilateral oophorectomy (n=201) in the Diabetes Prevention Program (DPP), a randomized placebo-controlled trial of lifestyle intervention and metformin among glucose intolerant adults. Associations between menopause and diabetes risk were evaluated using Cox proportional hazard models that adjusted for demographic variables (age, race/ethnicity, family history of diabetes, history of gestational diabetes mellitus), waist circumference, insulin resistance and corrected insulin response. Similar models were constructed after stratification by menopause type and hormone therapy (HT) use.
After adjustment for age, there was no association between natural menopause or bilateral oophorectomy and diabetes risk. Differences by study arm were observed in women who reported bilateral oophorectomy. In the lifestyle arm, women with bilateral oophorectomy had a lower adjusted hazard for diabetes (HR 0.19, 95% CI 0.04, 0.94), although observations were too few to determine if this was independent of HT use. No significant differences were seen in the metformin (HR 1.29, 95% CI 0.63, 2.64) or placebo arms (HR 1.37, 95% CI 0.74, 2.55).
Among women at high-risk for diabetes, natural menopause was not associated with diabetes risk and did not affect response to diabetes prevention interventions. In the lifestyle intervention, bilateral oophorectomy was associated with decreased diabetes risk.
PMCID: PMC3500880  PMID: 21709591
diabetes; impaired glucose tolerance; menopause; oophorectomy; women
20.  Effectiveness of Lifestyle Interventions for Individuals With Severe Obesity and Type 2 Diabetes 
Diabetes Care  2011;34(10):2152-2157.
Rates of severe obesity (BMI ≥40 kg/m2) are on the rise, and effective treatment options are needed. We examined the effect of an intensive lifestyle intervention (ILI) on weight loss, cardiovascular disease (CVD) risk, and program adherence in participants with type 2 diabetes who were severely obese compared with overweight (BMI 25 to <30 kg/m2), class I (BMI 30 to <35 kg/m2), and class II (BMI 35 to <40 kg/m2) obese participants.
Participants in the Action for Health in Diabetes (Look AHEAD) trial were randomly assigned to ILI or diabetes support and education (DSE). DSE participants received a less intense educational intervention, whereas ILI participants received an intensive behavioral treatment to increase physical activity (PA) and reduce caloric intake. This article focuses on the 2,503 ILI participants (age 58.6 ± 6.8 years).
At 1 year, severely obese participants in the ILI group lost −9.04 ± 7.6% of initial body weight, which was significantly greater (P < 0.05) than ILI participants who were overweight (−7.43 ± 5.6%) and comparable to class I (−8.72 ± 6.4%) and class II obese (−8.64 ± 7.4%) participants. All BMI groups had comparable improvements in fitness, PA, LDL cholesterol, triglycerides, blood pressure, fasting glucose, and HbA1c at 1 year. ILI treatment session attendance was excellent and did not differ among weight categories (severe obese 80% vs. others 83%; P = 0.43).
Severely obese participants in the ILI group had similar adherence, percentage of weight loss, and improvement in CVD risk compared with less obese participants. Behavioral weight loss programs should be considered an effective option for this population.
PMCID: PMC3177753  PMID: 21836103
22.  Effects of Intravenous Glucose Load on Insulin Secretion in Patients With Ketosis-Prone Diabetes During Near-Normoglycemia Remission 
Diabetes Care  2010;33(4):854-860.
Most patients with ketosis-prone type 2 diabetes (KPD) discontinue insulin therapy and remain in near-normoglycemic remission. The aim of this study was to determine the effect of glucotoxicity on β-cell function during remission in obese patients with KPD.
Age- and BMI-matched obese African Americans with a history of KPD (n = 8), severe hyperglycemia but without ketosis (ketosis-resistant type 2 diabetes, n = 7), and obese control subjects (n = 13) underwent intravenous infusion of 10% dextrose at a rate of 200 mg per m2/min for 20 h. β-Cell function was assessed by changes in insulin and C-peptide concentrations during dextrose infusion and by changes in acute insulin response (AIR) and first-phase insulin release (FPIR) to arginine stimulation before and after dextrose infusion.
The mean ± SD time to discontinue insulin therapy was 7.1 ± 1.7 weeks in KPD and 9.6 ± 2.3 weeks in ketosis-resistant type 2 diabetes (NS). During a 20-h dextrose infusion, changes in insulin, C-peptide, and the C-peptide–to–glucose ratio were similar among diabetic and control groups. During dextrose infusion, subjects with ketosis-resistant type 2 diabetes had greater areas under the curve for blood glucose than subjects with KPD and control subjects (P < 0.05). The AIR and FPIR to arginine stimulation as well as glucose potentiation to arginine assessed before and after dextrose infusion were not different among the study groups.
Near-normoglycemia remission in obese African American patients with KPD and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. At near-normoglycemia remission, patients with KPD displayed a pattern of insulin secretion similar to that of patients with ketosis-resistant type 2 diabetes and obese nondiabetic subjects.
PMCID: PMC2845041  PMID: 20067967
23.  Lack of Lipotoxicity Effect on β-Cell Dysfunction in Ketosis-Prone Type 2 Diabetes 
Diabetes Care  2009;33(3):626-631.
Over half of newly diagnosed obese African Americans with diabetic ketoacidosis (DKA) discontinue insulin therapy and go through a period of near-normoglycemia remission. This subtype of diabetes is known as ketosis-prone type 2 diabetes (KPDM).
To investigate the role of lipotoxicity on β-cell function, eight obese African Americans with KPDM, eight obese subjects with type 2 diabetes with severe hyperglycemia without ketosis (ketosis-resistant type 2 diabetes), and nine nondiabetic obese control subjects underwent intravenous infusion of 20% intralipid at 40 ml/h for 48 h. β-Cell function was assessed by changes in insulin and C-peptide concentration during infusions and by changes in acute insulin response to arginine stimulation (AIRarg) before and after lipid infusion.
The mean time to discontinue insulin therapy was 11.0 ± 8.0 weeks in KPDM and 9.6 ± 2.2 weeks in ketosis-resistant type 2 diabetes (P = NS). At remission, KPDM and ketosis-resistant type 2 diabetes had similar glucose (94 ± 14 vs. 109 ± 20 mg/dl), A1C (5.7 ± 0.4 vs. 6.3 ± 1.1%), and baseline AIRarg response (34.8 ± 30 vs. 64 ± 69 μU/ml). P = NS despite a fourfold increase in free fatty acid (FFA) levels (0.4 ± 0.3 to 1.8 ± 1.1 mmol/l, P < 0.01) during the 48-h intralipid infusion; the response to AIRarg stimulation, as well as changes in insulin and C-peptide levels, were similar among obese patients with KPDM, patients with ketosis-resistant type 2 diabetes, and nondiabetic control subjects.
Near-normoglycemia remission in obese African American patients with KPDM and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. A high FFA level by intralipid infusion for 48 h was not associated with β-cell decompensation (lipotoxicity) in KPDM patients.
PMCID: PMC2827521  PMID: 20028938
24.  Actos Now for the prevention of diabetes (ACT NOW) study 
Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.
602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.
Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.
ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.
Trial Registration
clinical identifier: NCT00220961
PMCID: PMC2725044  PMID: 19640291
25.  Factors Influencing the Handling of Insulin by the Isolated Rat Kidney 
Journal of Clinical Investigation  1978;62(1):169-175.
The renal handling of immunoreactive insulin was studied in the isolated perfused normothermic rat kidney to determine (a) the relative contributions of glomerular clearance and peritubular clearance to the renal clearance of insulin under different conditions, (b) what metabolic factors influence the ability of tubular cells to remove insulin from the glomerular filtrate and the peritubular circulation, and (c) whether the same factors influence the luminal and contraluminal uptake of insulin.
In control kidneys the organ clearance of insulin (OCi) was 974±63 μl/min (SEM), of which a maximum of 46% could theoretically be accounted for by filtration. OCi was not altered by fasting, lack of exogenous fuel (glucose), or the addition of cyanide. The glomerular filtration rate did not correlate with the OCi, but there was a significant (P < 0.001) negative correlation (r = −0.828) between the peritubular clearance and glomerular filtration rate. Both N-ethylmaleimide and cold (10°C) reduced the rate of insulin removal. Fractional excretion of filtered insulin (9.7±1.7% in controls) was not significantly altered by fasting or perfusing without glucose. In contrast, KCN increased fractional excretion of insulin to 41.9±3.7% whereas cold increased fractional excretion to 69.0±3.3%.
This study indicates that renal tubular cells remove insulin from the tubular lumen and the peritubular compartment. Furthermore, the data suggest that insulin removal by tubular cells is a temperature-sensitive process consisting of two different systems. The system associated with the luminal aspect of the cell appears to be dependent on oxidative metabolism, whereas the system associated with the contraluminal aspects of the cell appears to be independent thereof. Under several circumstances when the glomerular clearance of insulin falls thereby reducing the amount of insulin absorbed by the luminal aspect of the cell, contraluminal uptake increases, and a constant rate of insulin removal is maintained by the kidney.
PMCID: PMC371750  PMID: 659630

Results 1-25 (27)