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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.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.2337/dc12-1912
PMCID: PMC3687312  PMID: 23404297
2.  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 
Background
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).
Conclusions
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.
doi:10.1161/CIRCGENETICS.113.000042
PMCID: PMC4077278  PMID: 23861364
genomics; physiological; cholesterylester transfer protein genetics; triglycerides; behavior modification; lipoprotein
3.  FTO predicts weight regain in the Look AHEAD Clinical Trial 
International journal of obesity (2005)  2013;37(12):10.1038/ijo.2013.54.
Background
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.
Methods
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.
Results
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).
Conclusions
Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.
doi:10.1038/ijo.2013.54
PMCID: PMC3750057  PMID: 23628854
type 2 diabetes; obesity; weight loss, diet, genetics
4.  The long-term effectiveness of a lifestyle intervention in severely obese individuals 
The American journal of medicine  2013;126(3):236-242.e2.
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.amjmed.2012.10.010
PMCID: PMC3574274  PMID: 23410564
Severe obesity; weight loss; lifestyle intervention; diabetes; cardiovascular disease
5.  Acidosis: The Prime Determinant of Depressed Sensorium in Diabetic Ketoacidosis 
Diabetes Care  2010;33(8):1837-1839.
OBJECTIVE
The etiology of altered sensorium in diabetic ketoacidosis (DKA) remains unclear. Therefore, we sought to determine the origin of depressed consciousness in DKA.
RESEARCH DESIGN AND METHODS
We analyzed retrospectively clinical and biochemical data of DKA patients admitted in a community teaching hospital.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc10-0102
PMCID: PMC2909073  PMID: 20484127
6.  Hyperglycemic Crises in Adult Patients With Diabetes 
Diabetes Care  2009;32(7):1335-1343.
doi:10.2337/dc09-9032
PMCID: PMC2699725  PMID: 19564476
7.  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.
doi:10.2337/dc08-0509
PMCID: PMC2571050  PMID: 18694978
8.  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.
doi:10.1038/oby.2012.33
PMCID: PMC3632374  PMID: 22327053
weight loss; type 2 diabetes mellitus; principal components analysis
9.  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.
doi:10.1016/j.metabol.2010.09.010
PMCID: PMC3746516  PMID: 21134520
10.  A Comparison Study of Continuous Insulin Infusion Protocols in the Medical Intensive Care Unit: Computer-Guided Vs. Standard Column-Based Algorithms 
PURPOSE
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).
METHODS
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.
RESULTS
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).
CONCLUSION
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.
doi:10.1002/jhm.816
PMCID: PMC3733454  PMID: 20945468
diabetes; hospital; hyperglycemia; hypoglycemia; insulin infusion; intensive care unit
11.  Effectiveness of Lifestyle Interventions for Individuals With Severe Obesity and Type 2 Diabetes 
Diabetes Care  2011;34(10):2152-2157.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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).
RESULTS
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).
CONCLUSIONS
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.
doi:10.2337/dc11-0874
PMCID: PMC3177753  PMID: 21836103
13.  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.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc09-1687
PMCID: PMC2845041  PMID: 20067967
14.  Lack of Lipotoxicity Effect on β-Cell Dysfunction in Ketosis-Prone Type 2 Diabetes 
Diabetes Care  2009;33(3):626-631.
OBJECTIVE
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).
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc09-1369
PMCID: PMC2827521  PMID: 20028938
15.  Actos Now for the prevention of diabetes (ACT NOW) study 
Background
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.
Methods/Design
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.
Conclusion
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 trials.gov identifier: NCT00220961
doi:10.1186/1472-6823-9-17
PMCID: PMC2725044  PMID: 19640291
16.  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
17.  Direct measurement of proinsulin in human plasma by the use of an insulin-degrading enzyme 
Journal of Clinical Investigation  1971;50(9):1792-1799.
A method has been described for the direct measurement of proinsulin in human plasma. The method makes use of an insulin-degrading enzyme designated “insulin-specific protease (ISP)”, which is obtained from rat skeletal muscle. Under the conditions used, this enzyme rapidly degrades insulin and insulin-like polypeptides to nonimmunoassayable components, whereas proinsulin and proinsulin cleaved at position B54,55 are not appreciably affected. The incubation of plasma with ISP results in the disappearance of insulin, but not proinsulin, as demonstrated by column chromatography. Immunoassay of the plasma, therefore, before and after incubation, determines the values for the total immunoreactive substance (TIR) and for immunoreactive proinsulin (IRP), respectively. The values obtained for proinsulin levels are reproducible and compare closely with the more complicated column fractionation methods.
Proinsulin responses were studied in four normal subjects and one patient with an insulinoma after a glucose load. Fasting proinsulin levels varied widely in the normal subjects, and the levels rose more slowly than TIR levels after glucose. IRP levels in the patient with an insulinoma were very high and fell to normal after removal of the tumor.
The ISP method, therefore, appears to be suitable for the direct, accurate, and rapid determination of proinsulin and proinsulin-like materials in human plasma.
PMCID: PMC292103  PMID: 4327576
18.  The biological and immunological properties of pork and beef insulin, proinsulin, and connecting peptides 
Journal of Clinical Investigation  1970;49(5):979-987.
The recently discovered hormone precursors, pork and beef proinsulins, their respective connecting peptides, and beef proinsulin intermediates have been compared to insulin in their ability to stimulate the conversion of glucose-U-14C to 14CO2 and lipids in isolated fat cells. The concentrations of beef and pork proinsulins required to achieve the same biological effect were respectively, 15 and 10 times that of insulin. Beef proinsulin intermediates required only 2.6 times the concentration of insulin for the same effect. Pork and beef connecting peptides in high or low concentrations alone or in combination with proinsulin, insulin, or proinsulin intermediates showed no biological effect on the isolated fat cell system. The insulin-like activity of beef and pork proinsulins on the isolated fat cell system was not abolished with pancreatic trypsin or kallikrein inhibitors. Pork insulin antiserum inhibited the biological activity of pork insulin and proinsulin as well as that of beef insulin or proinsulin. Pork proinsulin antiserum also inhibited the insulin-like activity of both pork insulin and proinsulin. By the radioimmunoassay method, pork insulin antiserum bound only ¼ to [unk] as much proinsulin as insulin. Beef proinsulin intermediates, on the other hand, were found to react with the pork insulin antiserum to an extent nearly equal to that of insulin. These data suggest that (a) proinsulin exhibits its effect on the isolated fat cells independent of its conversion to insulin, (b) connecting peptides have no biological effect under present experimental conditions, and (c) in comparison to insulin, immunological reactivity of proinsulin is greater than its biological activity using our pork insulin antiserum; thus, the comparison of antibody specificity with the fat cell receptor specificity suggests that the biological site of action is different from the immunologic site.
Images
PMCID: PMC535770  PMID: 5309725
19.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
Objective
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.
Conclusions
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.
doi:10.1161/ATVBAHA.112.300346
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
20.  Menopause and risk of diabetes in the Diabetes Prevention Program 
Menopause (New York, N.Y.)  2011;18(8):857-868.
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/gme.0b013e31820f62d0
PMCID: PMC3500880  PMID: 21709591
diabetes; impaired glucose tolerance; menopause; oophorectomy; women

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