RAPID DEVELOPMENT OF IATROGENIC CUSHING SYNDROME IN A PATIENT ON RITONAVIR: THE ADVERSE METABOLIC CONSEQUENCE OF TOPICAL STEROID USE.

OBJECTIVE: Topical steroid use is common, but its association with Cushing syndrome is rare. We report the rapid development of iatrogenic Cushing syndrome in a patient on ritonavir who applied a moderate-potency topical steroid cream, triamcinolone, on his genital mucosa for treatment of phimosis. METHODS: Clinical and diagnostic challenges associated with topical steroid use are presented and discussed. RESULTS: A 41-year-old man with human immunodeficiency virus infection on stable antiretroviral therapy that included ritonavir, a cytochrome P450 3A4 inhibitor, presented with new onset diabetes and development of overt cushingoid features over a 4-week period. He reported no known history of steroid use. A midnight salivary cortisol using a quantitative enzyme immunoassay was obtained and reported at >15.0 µg/dL (normal, <0.112 µg/dL). However, free cortisol in a 24-hour urine collection was undetectable by high-performance liquid chromatography and morning plasma cortisol was also unexpectedly low at 1.1 µg/dL (normal, 4.5 to 23.0 µg/dL). Further investigation revealed that the patient had been applying a topical cream with triamcinolone acetonide (0.1%) on the glans penis for treatment of phimosis. The salivary enzyme immunoassay for cortisol appears to have detected the absorbed triamcinolone, a compound known to cross-react with cortisol in this assay. CONCLUSION: This case raises awareness on the severe metabolic consequence resulting from the seemingly benign use of a topical steroid medication when applied to the genital mucosa in the setting of stable therapy with ritonavir and illustrates the limitations of salivary cortisol enzyme immunoassays for the evaluation of Cushing syndrome in this setting.

Nonsevere Diabetic Ketoacidosis and Adrenal Insufficiency: Exploring the Impact of Glucocorticoid Replacement on Metabolic Outcomes and ICU Length of Stay.

BACKGROUND: There is a paucity of clinical data on corticosteroid replacement in patients with adrenal insufficiency who present with nonsevere noncomplicated diabetic ketoacidosis. CASE SUMMARY: We analyzed five consecutive admissions for diabetic ketoacidosis of mild/moderate severity due to insulin omission in a 21-year-old man with type 1 diabetes and stable Addison disease. Despite similar presentations, the approach to steroid replacement differed: maintenance/moderate doses of hydrocortisone (< 60 mg/d) or high stress-doses (≥ 120 mg/d). Resolution of diabetic ketoacidosis and ICU and hospital length of stay were prolonged when high-dose versus maintenance/moderate glucocorticoids were provided: 45.5, 47.0, and 63.0 versus 12.0, 24.5, and 31 hours, respectively. CONCLUSIONS: Although our findings remain hypothesis-generating, our case study raises awareness on the importance of categorizing diabetic ketoacidosis by severity and complication status when deciding on the intensity of steroid replacement in patients with stable Addison disease. Excessive glucocorticoid administration may delay the resolution of nonsevere and otherwise noncomplicated diabetic ketoacidosis and prolong ICU and hospital stays.

MANAGEMENT OF DIABETES DURING AIR TRAVEL: A SYSTEMATIC LITERATURE REVIEW OF CURRENT RECOMMENDATIONS AND THEIR SUPPORTING EVIDENCE.

OBJECTIVE: Individuals with diabetes are increasingly seeking pretravel advice, but updated professional recommendations remain scant. We performed a systematic review on diabetes management during air travel to summarize current recommendations, assess supporting evidence, and identify areas of future research. METHODS: A systematic review of the English literature on diabetes management during air travel was undertaken utilizing PubMed and MEDLINE. Publications regarding general travel advice; adjustment of insulin and noninsulin therapies; and the use of insulin pumps, glucometers and subcutaneous glucose sensors at altitude were included. Gathered information was used to create an updated summary of glucose-lowering medication adjustment during air travel. RESULTS: Sixty-one publications were identified, most providing expert opinion and few offering primary data (47 expert opinion, 2 observational studies, 2 case reports, 10 device studies). General travel advice was uniform, with increasing attention to preflight security. Indications for oral antihyperglycemic therapy adjustments varied. There were few recommendations on contemporary agents and on nonhypoglycemic adverse events. There was little consensus on insulin adjustment protocols, many antedating current insulin formulations. Most publications advocated adjusting insulin pump time settings after arrival; however, there was disagreement on timing and rate adjustments. Glucometers and subcutaneous glucose sensors were reported to be less accurate at altitude, but not to an extent that would preclude their clinical use. CONCLUSION: Recommendations for diabetes management during air travel vary significantly and are mostly based on expert opinion. Data from systematic investigation on glucose-lowering medication adjustment protocols may support the development of a future consensus statement. ABBREVIATIONS: CSII = continuous subcutaneous insulin infusion (device) DPP-4 = dipeptidyl peptidase 4 EGA = error grid analysis GDH = glucose dehydrogenase GOX = glucose oxidase GLP1 = glucagon-like peptide-1 NPH = neutral protamine Hagedorn SGLT2 = sodium-glucose cotransporter-2.

Lifestyle Intervention for Weight Loss and Cardiometabolic Changes in the Setting of Glucokinase Regulatory Protein Inhibition: Glucokinase Regulatory Protein-Leu446Pro Variant in Look AHEAD.

BACKGROUND: Glucokinase regulatory protein (GCKR) inhibitors offer a novel treatment approach for glucose control in diabetes mellitus; however, their cardiometabolic effects, particularly in relation to increased triglycerides and C-reactive protein (CRP) levels, are of concern. GCKR Leu446Pro is a common variant associated with reduced GCKR function, increased triglycerides, and CRP. METHODS AND RESULTS: We investigated whether a 1-year intensive lifestyle intervention (ILI) for weight loss would avert the unfavorable cardiometabolic effects associated with GCKR Leu446Pro when compared with a diabetes mellitus support and education arm in overweight/obese individuals with type 2 diabetes mellitus with triglyceride (n=3214) and CRP (n=1411) data participating in a randomized lifestyle intervention study for weight loss, Action for Health in Diabetes Mellitus (Look AHEAD). Once demographics, medication use and baseline adiposity, and fitness were accounted for, ILI did not modify the baseline association of GCKR-Leu446Pro with elevated triglycerides (ß±SE=0.067±0.013, P=1.5×10(-7) and ß±SE=0.052±0.015, P=5×10(-4)) or with elevated CRP (ß±SE=0.136±0.034, P=5.1×10(-5)and ß±SE=0.903±0.038, P=0.015) in the overall sample and Non-Hispanic Whites, respectively. The lack of a protective effect from ILI at 1 year when compared with diabetes mellitus support and education (ILI versus diabetes mellitus support and education interaction for triglyceride and CRP change, respectively: P=0.64 and 0.37 in the overall sample; P=0.27 and 0.05 in Non-Hispanic Whites) persisted after additional adjustment for changes in adiposity and fitness. CONCLUSIONS: Moderate improvements in adiposity and fitness with ILI did not mitigate the adverse cardiometabolic effects of GCKR inhibition in overweight/obese individuals with diabetes mellitus.

Improving Adiponectin Levels in Individuals With Diabetes and Obesity: Insights From Look AHEAD.

OBJECTIVE: This study investigated whether fitness changes resulting from lifestyle interventions for weight loss may independently contribute to the improvement of low adiponectin levels in obese individuals with diabetes. RESEARCH DESIGN AND METHODS: Look AHEAD (Action for Health in Diabetes) randomized overweight/obese individuals with type 2 diabetes to intensive lifestyle intervention (ILI) for weight loss or to diabetes support and education (DSE). Total and high-molecular weight adiponectin (adiponectins), weight, and cardiorespiratory fitness (submaximal exercise stress test) were measured in 1,397 participants at baseline and at 1 year, when ILI was most intense. Regression analyses examined the associations of 1-year weight and fitness changes with change in adiponectins. RESULTS: ILI resulted in greater improvements in weight, fitness, and adiponectins at 1 year compared with DSE (P < 0.0001). Weight loss and improved fitness were each associated with changes in adiponectins in men and women (P < 0.001 for all), after adjusting for baseline adiponectins, demographics, clinical variables, and treatment arm. Weight loss contributed an additional 4-5% to the variance of change in adiponectins than did increased fitness in men; in women, the contributions of improved fitness (1% greater) and of weight loss were similar. When weight and fitness changes were both accounted for, weight loss in men and increased fitness in women retained their strong associations (P < 0.0001) with adiponectin change. CONCLUSIONS: Improvements in fitness and weight with ILI were favorably but distinctly associated with changes in adiponectin levels in overweight/obese men and women with diabetes. Future studies need to investigate whether sex-specific biological determinants contribute to the observed associations.

A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.

Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent (n=1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 (ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: ß±SE=0.05±0.02, P=0.008; in non-Hispanic whites: 0.06±0.02, P=0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.

Fiber intake and plasminogen activator inhibitor-1 in type 2 diabetes: Look AHEAD (Action for Health in Diabetes) trial findings at baseline and year 1.

Plasminogen activator inhibitor 1 (PAI-1) is elevated in obese individuals with type 2 diabetes and may contribute, independently of traditional factors, to increased cardiovascular disease risk. Fiber intake may decrease PAI-1 levels. We examined the associations of fiber intake and its changes with PAI-1 before and during an intensive lifestyle intervention (ILI) for weight loss in 1,701 Look AHEAD (Action for Health in Diabetes) participants with dietary, fitness, and PAI-1 data at baseline and 1 year. Look AHEAD was a randomized cardiovascular disease trial in 5,145 overweight/obese patients with type 2 diabetes, comparing ILI (goal of ≥7% reduction in baseline weight) with a control arm of diabetes support and education. ILI participants were encouraged to consume vegetables, fruits, and grain products low in sugar and fat. At baseline, median fiber intake was 17.9 g/day. Each 8.3 g/day higher fiber intake was associated with a 9.2% lower PAI-1 level (P=0.008); this association persisted after weight and fitness adjustments (P=0.03). Higher baseline intake of fruit (P=0.019) and high-fiber grain and cereal (P=0.029) were related to lower PAI-1 levels. Although successful in improving weight and physical fitness at 1 year, the ILI in Look AHEAD resulted in small increases in fiber intake (4.1 g/day, compared with -2.35 g/day with diabetes support and education) that were not related to PAI-1 change (P=0.34). Only 31.3% of ILI participants (39.8% of women, 19.1% of men) met daily fiber intake recommendations. Increasing fiber intake in overweight/obese individuals with diabetes interested in weight loss is challenging. Future studies evaluating changes in fiber consumption during weight loss interventions are warranted.

Genetic modifiers of cardiorespiratory fitness response to lifestyle intervention.

PURPOSE: Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes risk and delays disease progression. We hypothesized that genetic variants modify fitness response to an intensive lifestyle intervention (ILI) in the Action for Health in Diabetes (Look AHEAD) randomized clinical trial, aimed to detect whether ILI will reduce cardiovascular events in overweight/obese subjects with type 2 diabetes compared with a standard of care. METHODS: Polymorphisms in established fitness genes and in all loci assayed on the Illumina CARe iSelect chip were examined as predictors of change in MET level, estimated using a treadmill test, in response to a 1-yr intervention in 3899 participants. RESULTS: We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with 1-yr METs response in ILI (0.19 ± 0.04 MET less improvement per minor allele copy; P = 1.9 × 10(-5)) and genotype-intervention interaction (P = 4.8 × 10(-3)). In the chipwide analysis, FKBP7 rs17225700 showed a significant association with ILI response among subjects not receiving beta-blocker medications (0.47 ± 0.09 METs less improvement; P = 5.3 × 10(-5)) and genotype-treatment interaction (P = 5.3 × 10(-7)). The Gene Relationships Among Implicated Loci pathway-based analysis identified connections between associated genes, including those influencing vascular tone, muscle contraction, cardiac energy substrate dynamics, and muscle protein synthesis. CONCLUSIONS: This is the first study to identify genetic variants associated with fitness responses to a randomized lifestyle intervention in overweight/obese diabetic individuals. RUNX1 and FKBP7, involved in erythropoesis and muscle protein synthesis, respectively, are related to change in cardiorespiratory fitness in response to exercise.

Do genetic modifiers of high-density lipoprotein cholesterol and triglyceride levels also modify their response to a lifestyle intervention in the setting of obesity and type-2 diabetes mellitus?: The Action for Health in Diabetes (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 as associated with HDL-C or triglyceride levels modify 1-year treatment response to an intensive lifestyle intervention, relative to a usual care of diabetes mellitus support and education. METHODS AND RESULTS: We evaluated 82 single-nucleotide polymorphisms, which represent 31 loci demonstrated by genome-wide association studies to be associated with HDL-C and triglycerides, in 3561 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 intensive lifestyle intervention (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 rs1535 variant, associated with low baseline HDL-C (P=0.017), was associated with HDL-C increases with intensive lifestyle intervention (0.0037) and had a nominal treatment interaction (P=0.035). Apolipoprotein B (rs693) and LIPC (rs8034802) single-nucleotide polymorphisms showed nominally significant associations with HDL-C and triglyceride changes with intensive lifestyle intervention and a treatment interaction (P<0.05). Phosphatidylglycerophosphate synthase-1 single-nucleotide polymorphisms (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 or obese individuals with diabetes mellitus. The effects of genetic factors on lipid changes may differ from the effects on baseline lipids and are modifiable by behavioral intervention.

Lifestyle intervention and/or statins for the reduction of C-reactive protein in type 2 diabetes: from the look AHEAD study.

OBJECTIVE: Cardiovascular risk remains high despite statin use. Overweight/obese diabetic persons usually have normal/low LDL-cholesterol but high C-reactive protein (CRP) levels. We aimed to examine the effects of intensive lifestyle intervention for weight loss (ILI) on CRP levels in overweight/obese diabetic individuals by statin use. DESIGN AND METHODS: Look AHEAD was a randomized trial in overweight/obese type 2 diabetic individuals testing whether ILI would reduce cardiovascular mortality, when compared to usual care. CRP changes in 1,431 participants with biomarker levels, who remained on or off statin treatment for 1 year, were evaluated. RESULTS: The reduction in CRP levels with ILI at 1 year in men and women on statins was -44.9 and -42.3%, respectively, compared to -13.7 and -21.0% for those on statins and usual care (P < 0.0001). At 1 year, median CRP levels were: 1.8 mg L(-1) in participants randomized to ILI on statin therapy; 2.6 mg L(-1) for those on statins randomized to usual care and 2.9 mg L(-1) for participants not on statins but randomized to ILI. Weight loss was associated with 1-year CRP reduction (P < 0.0001) in statin and nonstatin users. CONCLUSIONS: Our findings suggest that in overweight/obese diabetic persons, ILI and statin therapy may have substantial additive anti-inflammatory benefits.

Adiponectin and the mediation of HDL-cholesterol change with improved lifestyle: the Look AHEAD Study.

Adipose tissue dysfunction plays a key role in the development of the metabolic abnormalities characteristic of type 2 diabetes (T2DM) and participates actively in lipid metabolism. Adiponectin, found abundantly in circulation and a marker of adipose health, is decreased in obese persons with T2DM. We investigated whether the changes in adiponectin with an intensive lifestyle intervention (ILI) for weight loss could potentially mediate the increase in low HDL-cholesterol (HDL-C) with ILI. Adiponectin and its fractions were determined using an ELISA with selective protease treatment in 1,397 participants from Look AHEAD, a trial examining whether ILI will reduce cardiovascular events in overweight/obese subjects with T2DM when compared with a control arm, diabetes support and education (DSE). Multivariable regression and mediational analyses were performed for adiponectin and its high-molecular-weight (HMW) and non-HMW fractions. ILI increased baseline HDL-C by 9.7% and adiponectin by 11.9%; changes with DSE were 1.3% and 0.2%, respectively (P < 0.0001). In a model including changes in weight, fitness, triglycerides, and glucose control and that adjusted for demographics and medical history, adiponectin changes remained significantly associated with HDL-C change. Data supported the contribution of changes in both HMW- and non-HMW-adiponectin to the improvement in HDL-C with ILI.

The effect of various intensities of physical activity and chronic inflammation in men and women by diabetes status in a national sample.

Moderate-to-vigorous physical activity (MVPA) has been shown to be inversely associated with C-reactive protein (CRP); however, the association between light intensity physical activity (LPA), and CRP is unknown. Our findings suggest that focusing on increasing MVPA, relative to LPA, may have a greater impact on inflammation regardless of diabetes status.

Metabolic factors, adipose tissue, and plasminogen activator inhibitor-1 levels in type 2 diabetes: findings from the look AHEAD study.

OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1) production by adipose tissue is increased in obesity, and its circulating levels are high in type 2 diabetes. PAI-1 increases cardiovascular risk by favoring clot stability, interfering with vascular remodeling, or both. We investigated in obese diabetic persons whether an intensive lifestyle intervention for weight loss (ILI) would decrease PAI-1 levels independently of weight loss and whether PAI-1 reduction would be associated with changes in fibrinogen, an acute phase reactant, or fibrin fragment D-dimer (D-dimer), a marker of ambient coagulation balance. METHODS AND RESULTS: We examined 1-year changes in PAI-1, D-dimer, and fibrinogen levels; adiposity; fitness; glucose; and lipid control with ILI in 1817 participants from Look AHEAD, a randomized trial investigating the effects of ILI, compared with usual care, on cardiovascular events in overweight or obese diabetic persons. Median PAI-1 levels decreased 29% with ILI and 2.5% with usual care (P < 0.0001). Improvements in fitness, glucose control, and high-density lipoprotein cholesterol were associated with decreased PAI-1, independently of weight loss (P = 0.03 for fitness, P < 0.0001 for others). Fibrinogen and D-dimer remained unchanged. CONCLUSIONS: Reductions in PAI-1 levels with ILI in obese diabetic individuals may reflect an improvement in adipose tissue health that could affect cardiovascular risk without changing fibrinogen or d-dimer levels. Clinical Trial Registration- URL: http://clinicaltrials.gov/ct2/show/NCT00017953. Unique identifier: NCT00017953.