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Lack of healthcare insurance is an important factor for poor glycemic control in persons with diabetes. However, a large proportion of insured people also have inadequate glycemic control. This study was conducted to assess factors associated with poor glycemic control in persons with type 2 diabetics (T2D) who received full healthcare coverage through their employer.The study included employees and spouses with T2D who participated in an annual health assessment in 20 and had medical coverage ≥12 consecutive months prior to the assessment. T2D was defined from ICD codes in claims, self-reported physician diagnosis, or having fasting glucose > 125 mg/dL or HbA1C > 6.4%. A stepwise multinomial logistic regression model was used to assess associations of healthcare engagement, diet, smoking and socioeconomic status with glycemic control. The 2,981 participants included 16% (n=484) with HbA1C > 8.5% and 27% (n=800) with HbA1C 7 to 8.5%. We found that HbA1C > 8.5% was associated with age, sex, years since last physical exam, number of complications, number of medications, and physical activity. The regression model results are shown in the figure. We conclude that poor glycemic control is common among persons with T2D despite good healthcare coverage. We identified factors associated with poor glycemic control in this population that may help design strategies to improve glycemic control. Disclosure C.M.Rowland: Employee; Quest Diagnostics, Stock/Shareholder; Quest Diagnostics. J.Z.Louie: None. D.Shiffman: Employee; Quest Diagnostics, Stock/Shareholder; Quest Diagnostics. R.Garg: None. E.Bernal-mizrachi: None. M.J.Mcphaul: Employee; Quest Diagnostics.

Poor socioeconomic status and inadequate insurance coverage may affect an individual’s ability to utilize healthcare services. This study was conducted to evaluate whether the type of insurance coverage is associated with missed appointments for diabetes care. Data analysis included all patients with diabetes mellitus (DM) managed at a major academic center between Jan 2015 and Dec 2020. Association between insurance coverage and proportion of missed appointments was evaluated using analysis of covariance with adjustments for demographic variables and social determinants of health. The relationship between proportion of missed appointments and glycemic control was also evaluated in multivariate analyses. The final dataset included 30,633 patients, out of which 14,064 (46%) reported commercial insurance, 13,376 (44%) reported Medicare and 3,193 (10%) reported Medicaid coverage. Medicaid group was identified to have the highest proportion of Spanish-speakers, African Americans, women, current smokers and single individuals. Proportion of missed appointments was 18.1 ± 18.1% in Medicaid covered patients as compared to 12.1 ± 15.3% among commercially insured and 10.2 ± 14.1% among Medicare covered patients (p Disclosure R.Radhakrishnan: None. W.H.Cade: None. E.Bernal-mizrachi: None. R.Garg: None.

The ADA recommends an A1C 8.5% (poor control) were included. Patients with improved glycemic control (current A1C ≤8.5%) were compared with those with lack of improvement (current A1C >8.5%) . On multivariate logistic regression analysis including all variables in the model, independent predictors of lack of improvement were: younger age (OR 0.89 per 1-SD [12 years]; 95 % CI 0.79 - 1.00) , female gender (1.30, 1.- 1.56) , presence of hypertension (1.29, 1.- 1.55) , Black race (1.32, 1.- 1.68, White as reference) , low income area code (1.86,1.28 - 2.68, high as reference) and insurance coverage other than Medicare (1.32, 1.- 1.66) . Presence of current smoking was associated with a paradoxical improvement in A1C (0.69, 0.47 - 0.99) . We conclude that socioeconomic factors like income, insurance coverage and neighborhood are associated with lack of improvement in A1C. Further studies need to identify specific modifiable socioeconomic factors. Disclosure R. Garg: None. J.Z. Louie: None. D. Shiffman: Employee; Quest Diagnostics. Stock/Shareholder; Quest Diagnostics. C.M. Rowland: Employee; Quest Diagnostics. Stock/Shareholder; Quest Diagnostics. M.J. McPhaul: Employee; Quest Diagnostics. E. Bernal-Mizrachi: None. N. Kenyon: Research Support; Elodon Phamaceutical, Takeda Pharmaceutical Company Limited.

While diabetes and admission blood glucose (BG) are established risk factors for adverse outcomes during hospitalization for COVID-19, reports on the impact of prior glycemic control have been variable. We examined the relationship between acute and chronic glycemia on risk of ICU admission, mechanical ventilation (MV) , and mortality among 1,786 patients with diabetes or hyperglycemia (BG > 180 mg/dl twice during any 24-hr period during hospitalization) admitted from March 2020 to February 2021 with COVID-at 5 large university hospitals in the eastern U.S. The cohort was 51.3% male, 53.3% White, 18.8% Black, 29.3% Hispanic, with age = 64.8 ± 13.8 y, BMI = 31.5 ± 7.9 kg/m2, admission BG = 216 ± 134 mg/dl, and HbA1c = 8.1 ± 2.2%. During hospitalization, 38.9% were admitted to the ICU, 22.9% received MV, and 10.6% died. In multivariate regression analysis, among demographic factors, age was the strongest risk factor for in-hospital mortality (OR = 1.per year [95% CI: 1.04, 1.06]) , and Hispanic ethnicity was the greatest risk factor for ICU admission (OR = 1.45 [95% CI: 1.16, 1.80]) and intubation (OR = 1.64 [95% CI: 1.28, 2.10]) . Higher BMI (p = 0.005) and admission BG (p = 0.014) were associated with increased risk of mortality, but HbA1c was not. The glycemic gap (GG) , defined as admission BG minus estimated average BG based on HbA1c, was a stronger predictor of mortality than either admission BG or HbA1c alone. Mortality rate was 5.7% for GG < -20 mg/dl; 12.2% for GG = -20 to < 20 mg/dl; 12.4% for GG = 20 to < 100 mg/dl; and 16.1% for GG ≥ 100 mg/dl (p for trend < 0.001) . Conclusion: Among patients with diabetes or hyperglycemia admitted for COVID-19, in addition to previously established risk factors for poor outcomes (age, Hispanic ethnicity, and BMI) , we found that GG is a stronger predictor of in-hospital mortality than blood glucose alone. This suggests that relative hyperglycemia, as measured by the admission GG, is an important marker of disease severity in COVID-and potentially other serious illnesses. Disclosure M.E.Mcdonnell: Advisory Panel; Everlywell, Inc., Research Support; Lilly, Stock/Shareholder; Abbott Diabetes. G.P.Westcott: None. D.C.Simonson: Stock/Shareholder; GI Windows, Phase V Technologies, Inc. G.Gopalakrishnan: Research Support; Eli Lilly and Company, Spruce Biosciences. R.Garg: None. J.Mitri: Consultant; dairy management, Lnutra. R.S.Weinstock: Research Support; Boehringer Ingelheim International GmbH, Dexcom, Inc., Diasome, Eli Lilly and Company, Insulet Corporation, Kowa Pharmaceuticals America, Inc., Medtronic, Novo Nordisk, Tandem Diabetes Care, Inc., Tolerion, Inc. M.Greenfield: None. N.E.Palermo: Research Support; Dexcom, Inc. R.Radhakrishnan: None. Funding Brigham-TechFoundation, Cambridge, MA 2021

People with diabetes (DM) hospitalized with COVID-19 infection have a 2-3 fold higher risk of death compared with those without DM, and mechanical ventilation (MV) has been identified as a major risk factor for death. While stress hyperglycemia (StH) has been established as a risk factor for death in some critically ill cohorts, it is not a well-established risk factor for MV in COVID-19. The COVIDEastDM consortium pooled data from 5 academic hospitals on the East Coast of the US to study the relationship between hyperglycemia and COVID-19 outcomes. Data were obtained retrospectively from electronic records of adults with COVID-19 and either DM or StH (defined in this cohort as day-1 admission blood glucose >180 mg/dl and A1c Disclosure M. E. Mcdonnell: Stock/Shareholder; Spouse/Partner; Abbott Diabetes. N. E. Palermo: None. R. Radhakrishnan: None. G. P. Westcott: None. R. S. Weinstock: Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. R. Garg: None. D. C. Simonson: Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. G. Cromwell: None. G. Gopalakrishnan: None. M. Greenfield: None. M. Johnson: None. S. R. Katta: None. J. Lebastchi: None. J. Mitri: Consultant; Self; L-Nutra. Funding TechFoundation; Brigham Education Institute

Type 2 diabetes mellitus (T2DM) is a progressive disease with many patients requiring insulin treatment. Basal insulin (BI) is often added first followed by escalation to a multiple subcutaneous insulin injection (MSI) regimen. However, many patients with T2DM struggle managing the MSI regimen. As a result, their glycemic control remains poor after starting MSI. Our study investigates whether switching back to BI alone would improve glycemic control. Patients with T2DM and A1C ≥9.0% on MSI regimen seen in our clinic over two years were included in this analysis. Main study outcome was the A1C after ≥3 months of switching back to BI as compared to continuing MSI. We found 24 patients who were switched from MSI to BI and compared them with 58 patients who were continued on MSI (see Table). There were no significant differences at baseline between the two groups. On follow-up, the BI group had a mean change in A1C (%) of -1.6 ± 2.0 compared to -0.7 ± 1.5 in the MSI group. In addition, the daily dose of prescribed insulin on follow-up was lower in the BI group at 46 ± 14 units/day compared to 90 ± 70 units/day in the MSI group. Hypoglycemia rates were also lower in the BI group at 12% compared to 20% in the MSI group. We conclude that simplification of insulin regimen may improve A1C and decrease the risk of hypoglycemia in patients poorly controlled on MSI regimen. The improved glycemic control is likely related to improved adherence and lower risk of errors. Disclosure A. Arunachalam: None. R. Garg: None.

Objective: Diabetes-related distress is present in a high proportion of people with type 2 diabetes mellitus (T2DM). We hypothesized that complexity of the antidiabetic medication regimen is a factor that increases diabetes-related distress. Research Design and Methods: We studied 74 consecutive patients with T2DM managed at a tertiary care center. Patients were screened for diabetes-related distress using the Diabetes Distress Scale-2 (DDS-2). A Diabetes Medication Complexity Scoring (DMCS) system was developed to objectively assess the diabetes medication complexity. Based on DMCS, participants were categorized into one of three groups: low (n = 26), moderate (n = 22) and high (n = 26) medication complexity. Results: The prevalence of diabetes-related distress (DDS-2 ≥6) was 34.6% in the low, 36.4% in the moderate, and 69.2% in the high complexity groups (χ2(2) = 7.75, p= 0.021). Complexity groups were similar on sociodemographic characteristics, diabetes duration, BMI and blood pressure as well as the prevalence of hypertension, hyperlipidemia and hypoglycemic episodes over the last year (ps>0.05). The prevalence of microvascular complications varied as a function of low (28%), moderate (45%), and high (76%) regimen complexity (χ2(2) = 11.8, p = 0.003). One-way ANOVA showed significant complexity group differences for HbA1c (F(2,70) = 5.47, p = 0.006) with higher HbA1c in the high and moderate complexity groups than in the low group. Analysis of covariance adjusting for HbA1c showed that DDS-2 significantly differed as a function of complexity group (F (2,69) = 3.93, p = .024). The model explained 16.2% of the variance in DDS-2 (R2 = 0.162). Post hoc analyses revealed that diabetes-related distress was significantly greater for the high (DDS-2 = 6.6) complexity group compared to the moderate complexity group (DDS-2 = 4.5) (p = .031). Conclusions: A complex antidiabetic medication regimen is associated with high levels of diabetes distress. Disclosure M. Luzuriaga: None. R. Leite: None. H. Ahmed: None. P. G. Saab: None. R. Garg: None.

Glycemic control in patients with diabetes mellitus receiving total parenteral nutrition (TPN) can be challenging due to multiple factors. These patients often have a high burden of illness and receive medications that raise blood glucose (BG) levels. Moreover, TPN delivers a large amount of glucose directly into the systemic circulation without the benefit of incretin effect. Therefore, relatively large amounts of insulin are expected to be required for glycemic control. However, there are no studies to guide insulin dosing in patients with diabetes being started on TPN. We conducted a retrospective study including all patients with diabetes admitted to our hospital over a 1-year period who received TPN for ≥ 3 days. The goal of this study was to estimate a safe starting dose of insulin for TPN. Patients receiving enteral nutrition along with TPN were excluded. Insulin doses and blood glucose levels on the last day of TPN were used for data analysis. We found 25 patients who fulfilled our inclusion/exclusion criteria. All patients had type 2 diabetes and were receiving antidiabetic drugs before hospitalization. Mean age was 68 ± 7 years, 56% were men, 80% were White, 44% had microvascular and 44% had macrovascular complications. Mean BMI was 26.7 ± 6.7 kg/m2, systolic BP 131 ± 27 mmHg, diastolic BP 65 ± 15 mmHg, HbA1c 7.7 ± 2.3% and serum creatinine 2.7 ± 3.3 mg/dl. The mean daily BG on TPN was 212 ± 47 mg/dl. Out of 171 BG values available on the last day of TPN, 116 (68%) were >180 mg/dl, 4 (2%) were Disclosure R. Garg: None. A. Arunachalam: None. L.E. Bermudez: None. M. Ramirez: None.

Cardiovascular (CV) disease fatality rates are higher for women compared with men with diabetes despite lower rates of obstructive coronary artery disease (CAD). Impaired coronary flow reserve (CFR), the ratio of adenosine-stimulated to rest myocardial blood flow (MBF), is an indicator of coronary microvascular dysfunction and predicts major adverse CV events. We performed a post hoc analysis to determine whether there was a sex disparity in coronary microvascular dysfunction among 46 men and 27 women with well-controlled type 2 diabetes and without clinical evidence of obstructive CAD. We found that women had a higher rest MBF, lower CFR, and worse diastolic function compared with men. In addition, rest MBF was positively correlated with worse diastolic function in women. We previously showed that mineralocorticoid blockade improved CFR in men and women with type 2 diabetes, implicating aldosterone in the pathophysiology of coronary microvascular dysfunction. We therefore examined aldosterone levels and found that women had larger increases in aldosterone in response to an angiotensin-II infusion than did men. In conclusion, among individuals with type 2 diabetes and good cardiometabolic control, women had worse myocardial perfusion and diastolic function compared with men. The greater aldosterone responsivity in women may be a mechanism for this sex effect.

IntroductionDiabetes-related distress is present in a high proportion of people with type 2 diabetes mellitus. We hypothesized that complexity of the antidiabetic medication regimen is a factor that is associated with diabetes-related distress.Research design and methodsThis was a retrospective study including a group of 74 patients managed at a tertiary care center. Patients with type 1 diabetes mellitus, steroid-induced diabetes, post-transplant diabetes, and other types of diabetes were excluded. Patients were screened using the Diabetes Distress Scale-2 (DDS-2). A Diabetes Medication Complexity Scoring (DMCS) system was developed to objectively assess the diabetes medication complexity. Based on DMCS, participants were categorized into three groups: low (n=26), moderate (n=22), and high (n=26) medication complexity.ResultsComplexity groups were similar in sociodemographic characteristics, diabetes duration, body mass index, and blood pressure as well as the prevalence of hypertension, hyperlipidemia and hypoglycemic episodes. However, there were significant differences for HbA1c with higher HbA1c in the high and moderate complexity groups than in the low group (p=0.006). The microvascular complications were also more common in higher complexity groups (p=0.003). The prevalence of diabetes-related distress (DDS-2 ≥6) was 34.6% in the low, 36.4% in the moderate and 69.2% in the high complexity groups (p=0.021). There were significant differences in DDS-2 score among complexity groups (p=0.009), with higher DDS-2 score in the high complexity group compared with the moderate (p=0.008) and low complexity groups (p=0.009). The difference in DDS-2 score remained significant after adjusting for HbA1c (p=0.024) but did not reach statistical significance after controlling for both HbA1c and microvascular complications (p=0.163).ConclusionsA complex antidiabetic medication regimen may be associated with high levels of diabetes-related distress.

Aim This study was conducted to evaluate the effect of continued follow-up by a hospital diabetes team on HbA1c at 1-year after discharge. Methods Adults with HbA1c ≥8% (64 mmol/mol), undergoing an elective surgery, were treated in the perioperative period and randomized to continued care (CC) or the usual care (UC) after discharge. Patients in the CC group received weekly to monthly phone calls from a diabetes specialist nurse practitioner (NP) to review their home blood glucose values, diet, exercise, and medications. Patients in the UC group followed with their diabetes care providers. Results Out of 151 patients, 77 were randomized to the CC group and 74 to the UC group. HbA1c (%) at 1-year was 8.2 ± 1.4 in the CC group and 8.5 ± 1.5 in the UC group (p = NS). Change in HbA1c from baseline was similar between the groups; −0.7 ± 1.4 in the CC versus −0.7 ± 1.5 in the UC group (p = NS). A higher number of calls was not associated with lower HbA1c or reduction in HbA1c. There were 41 insulin-treated patients in the CC group and 53 in the UC group and among them, HbA1c reduction was 0.5 ± 1.5 and 0.6 ± 1.3 respectively (p = NS). Conclusions Optimal perioperative treatment of diabetes is associated with an improvement in HbA1c but continued follow-up by a hospital diabetes team after discharge does not have an additional impact on long-term glycemic control. ClinicalTrials.gov identifier NCT02065050.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing, especially in the elderly population. Many of these patients have co-morbidities like renal insufficiency, cognitive impairment and lack of social support, increasing the risk of hypoglycemia. Moreover, the benefits of tight glycemic control have not been established in the elderly. Therefore, the American Diabetes Association recommends relaxed glycemic goals (HbA1c ∼8%) in the elderly population. De-intensification of diabetes treatment is recommended to prevent potential harm. We conducted a retrospective study to evaluate the rate of de-intensification of antidiabetic treatment in patients aged ≥75 years with HbA1c ≤7% at the time of their clinic visits. All patients with ≥2 clinic visits over 1-year period at a major academic diabetes center were included. Out of 1,417 unique patients treated during 2017, 174 were ≥75 years old on the day of their last clinic visit. Out of these, 80 patients had an HbA1c ≤7%. Medical records of these 80 patients were manually reviewed for comorbidities, hypoglycemic episodes and drug therapy. A mention of de-intensification of antidiabetic treatment was found in physicians’ notes in only 12 cases. After excluding those with type 1 diabetes, inadequate documentation or controlled on medications without hypoglycemia potential, we found 36 patients treated with a sulfonylurea drug or insulin. Only 10 (27%) patients were advised to reduce the dose of sulfonylurea drug or insulin after an HbA1c Disclosure D.V. Pirela: None. R. Garg: None.

Factors affecting utilization of diabetes care are not well-studied. This information may help develop strategies to improve the efficiency of healthcare systems. We conducted a study to determine factors associated with repeatedly missing an appointment at a major diabetes care center. Data were obtained from electronic medical records. All patients with two or more appointments during the year 2017 were included in analysis. Patients who missed ≥50% of their clinic visits without cancelling an appointment were defined as the repeatedly missed appointment (RMA) group and those who missed Disclosure R. Garg: None. W.H. Cade: None. E. Bernal-Mizrachi: None.

The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid-binding protein 4 (FABP4). Fabp4-deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted.

Several studies have demonstrated the benefits of glycemic control in the perioperative period and there is ongoing interest in development of systematic approaches to achieving glycemic control. This review discusses currently available data and proposes a new approach to the management of hyperglycemia in the perioperative period. In a recent study, we demonstrated that early preoperative identification of patients with poorly controlled diabetes and proactive treatment through various phases of surgery improves glycemic control, lowers the risk of surgical complications, and decreases the length of hospital stay. Implementation of a perioperative diabetes program that systematically identifies and treats patients with poor glycemic control early in the preoperative period is feasible and improves clinical care of patients undergoing elective surgery.

Background Patients with metabolic syndrome (MetS) are at increased risk of asymptomatic hyperuricemia (i.e., elevated serum uric acid (SUA) level without gout) and cardiovascular disease. We conducted a cross-sectional study to examine associations between SUA levels and coronary flow reserve and urate deposits in carotid arteries in patients with asymptomatic hyperuricemia and MetS. Methods Adults aged ≥40 years with MetS and SUA levels ≥6.5 mg/dl, but no gout, were eligible. Using a stress myocardial perfusion positron emission tomography (PET), we assessed myocardial blood flow (MBF) at rest and stress and calculated coronary flow reserve (CFR). CFR

Objectives Dual-energy CT (DECT) scan is a sensitive and specific tool used to visualise and quantify monosodium urate (MSU) crystal deposits in the joints. Few studies have examined MSU crystal deposits in patients with asymptomatic hyperuricemia (ie, hyperuricemia in the absence of gout) using DECT. Methods We conducted a prospective, non-interventional cross-sectional study to detect MSU crystal deposits on DECT scans among patients with asymptomatic hyperuricemia. We also examined patient factors associated with subclinical MSU crystal deposits. Out of 130 subjects aged ≥40 years with metabolic syndrome screened for serum uric acid (sUA) levels ≥6.5 mg/dL, 46 underwent a foot/ankle DECT scan. Results The mean age of the study participants was 62 (±8) years, 41% were men and the mean sUA level was 7.8 (±1.0) mg/dL. Seven (15%) of 46 patients had MSU crystal deposits on DECT with a mean total volume of 0.13 (±0.14) cm 3 . In the univariable logistic regression analysis, older age had a significant association with presence of MSU crystal deposits (OR 1.20, 95% CI 1.03 to 1.39), but sUA did not (OR 1.36, 95% CI 0.63 to 2.95). In the univariable analysis, sUA levels showed a trend towards a modest linear association (β=0.11, P=0.09) with total volume of MSU crystal deposits. Conclusions Fifteen per cent of patients with asymptomatic hyperuricemia had subclinical MSU crystal deposits on foot/ankle DECT scans. Older age, but not sUA, was significantly associated with presence of subclinical MSU crystal deposits among patients with asymptomatic hyperuricemia. Clinical significance of these subclinical MSU crystal deposits needs to be determined.

Objective The hippocampus is crucial for paired-associate learning. Obesity is associated with increased mineralocorticoid receptor (MR) activity in peripheral and possibly central tissues, decreased hippocampal size in humans, and impaired hippocampal learning in rodents. The MR is expressed in hippocampal neurons, and MR blockade improves hippocampal learning in obese animals. The goal of the study was to determine whether MR blockade would modulate paired-associate learning in men and women with obesity. Methods Men and women ages 20-61 years with BMI between 30-45 kg/m2 were randomly assigned to placebo (n = 11; 7 women) or 50 mg spironolactone daily (n = 12; 7 women) for six weeks. At baseline and post-treatment, subjects underwent a clinical and hormonal evaluation. They also underwent a computerized task that assesses paired-associate learning and has been shown by functional magnetic resonance imaging to activate the hippocampus. Results In an ANCOVA model that adjusted for baseline paired-associate learning, age, and race, spironolactone treatment was associated with a significant (P = 0.043) improvement in hippocampal memory as compared to placebo treatment. Conclusions Our findings demonstrate, for the first time, that blocking MR with chronic, low-dose spironolactone treatment improves paired-associate learning in individuals with obesity, suggesting that MR activation contributes to hippocampal memory modulation in humans.

Plasminogen activator inhibitor-1 (PAI-1) is implicated in the pathophysiology of cardiovascular disease (CVD) and increased in individuals with type 2 diabetes mellitus (T2DM). Adipose tissue produces PAI-1, and pericardial fat is a CVD risk factor. We sought to determine the relationship between PAI-1 and pericardial fat in males and females with well-controlled T2DM.The study population consisted of 32 males and 19 females, aged 35-70 years with T2DM, without clinical evidence of CVD or other active medical problems except for hypertension. Subjects were studied under good cardiometabolic control. Study procedures included fasting blood work and cardiovascular imaging. Cardiac magnetic resonance imaging of the heart was used to identify and quantify pericardial fat from the bifurcation of the pulmonary trunk to the last slice containing cardiac tissue.PAI-1 was positively correlated with pericardial fat (β = 0.72, r = 0.72, P 0.001) as well as with homeostatic model assessment of insulin resistance (r = 0.31, P = 0.03) and serum triglycerides (r = 0.27, P = 0.05). In a multivariable regression model, controlling for insulin sensitivity, triglycerides, and body mass index, pericardial fat was independently associated with PAI-1 (β = 0.80, P 0.001).PAI-1 is positively associated with pericardial fat in individuals with T2DM.

Accumulating evidence shows an increase in insulin resistance on salt restriction. We compared the effect of low salt diet on insulin resistance in salt-sensitive versus salt-resistant hypertensive subjects. We also evaluated the relationship between salt sensitivity of blood pressure and salt sensitivity of insulin resistance in a multivariate regression model. Studies were conducted after 1 week of high salt (200 mmol per day sodium) and 1 week of low salt (10 mmol per day sodium) diet. Salt sensitivity was defined as the fall in systolic blood pressure >15 mm Hg on low salt diet. The study includes 389 subjects (44% women; 16% blacks; body mass index, 28.5±4.2 kg/m 2 ). As expected, blood pressure was lower on low salt (129±16/78±9 mm Hg) as compared with high salt diet (145±18/86±10 mm Hg). Fasting plasma glucose, insulin, and homeostasis model assessment were higher on low salt diet (95.4±19.4 mg/dL; 10.8±7.3 mIU/L; 2.6±1.9) as compared with high salt diet (90.6±10.8 mg/dL; 9.4±5.8 mIU/L; 2.1±1.4; P P =NS). On multivariate regression analysis, change in systolic blood pressure was not associated with change in homeostasis model assessment after including age, body mass index, sex, change in serum and urine aldosterone, and cortisol into the model. We conclude that the increase in insulin resistance on low salt diet is not affected by salt sensitivity of blood pressure.

Reduced coronary flow reserve (CFR), an indicator of coronary microvascular dysfunction, is seen in type 2 diabetes mellitus (T2DM) and predicts cardiac mortality. Since aldosterone plays a key role in vascular injury, the aim of this study was to determine whether mineralocorticoid receptor (MR) blockade improves CFR in individuals with T2DM. Sixty-four men and women with well-controlled diabetes on chronic ACE inhibition (enalapril 20 mg/day) were randomized to add-on therapy of spironolactone 25 mg, hydrochlorothiazide (HCTZ) 12.5 mg, or placebo for 6 months. CFR was assessed by cardiac positron emission tomography at baseline and at the end of treatment. There were significant and similar decreases in systolic blood pressure with spironolactone and HCTZ but not with placebo. CFR improved with treatment in the spironolactone group as compared with the HCTZ group and with the combined HCTZ and placebo groups. The increase in CFR with spironolactone remained significant after controlling for baseline CFR, change in BMI, race, and statin use. Treatment with spironolactone improved coronary microvascular function, raising the possibility that MR blockade could have beneficial effects in preventing cardiovascular disease in patients with T2DM.

Objective Observational studies suggest that hydroxychloroquine (HCQ) may reduce the risk of developing diabetes mellitus in patients with rheumatoid arthritis (RA). We examined the effect of HCQ on insulin resistance in subjects without diabetes mellitus with stable RA. Methods Twenty-three RA subjects not currently using HCQ completed a 16-week, double-blind crossover study. Subjects were randomly allocated to receive HCQ (6.5 mg/kg/day) or placebo for the first 8 weeks, followed by crossover to the other arm for the final 8 weeks. Subjects underwent oral glucose tolerance testing and fasting lipid measurements at baseline, 8 weeks, and 16 weeks. The change ± SD from baseline in insulin sensitivity index (ISI), homeostatic model assessment for insulin resistance (HOMA-IR), and lipid parameters were compared between placebo and HCQ using linear regression. Results The mean patient age was 56 years, with 96% women, and the median body mass index was 26.0 kg/m2. After 8 weeks of HCQ, the mean ± SD ISI increase was 0.4 ± 2.9 compared with a small increase during placebo of 0.14 ± 3.1 (adjusted P = 0.785), and the mean ± SD HOMA-IR decrease was 0.3 ± 1.5 during HCQ versus a decrease of 0.42 ± 1.4 during placebo (adjusted P = 0.308). Small decreases in total cholesterol (12.7 mg/dl) and low-density lipoprotein (LDL) cholesterol (12.4 mg/dl) were observed during the HCQ treatment periods (both adjusted P < 0.05 compared to placebo). Conclusion HCQ use for 8 weeks in patients without diabetes mellitus with stable RA produced no significant change in insulin resistance. We observed small and statistically significant improvements in total and LDL cholesterol during HCQ treatment.

OBJECTIVE To evaluate the relationship between preoperative A1C and clinical outcomes in individuals with diabetes mellitus undergoing noncardiac surgery. RESEARCH DESIGN AND METHODS Data were obtained from the National Surgical Quality Improvement Program database and the Research Patient Data Registry of the Brigham and Women’s Hospital. Patients admitted to the hospital for ≥1 day after undergoing noncardiac surgery from 2005 to 2010 were included in the study. RESULTS Of 1,775 patients with diabetes, 622 patients (35%) had an A1C value available within 3 months before surgery. After excluding same-day surgeries, patients with diabetes were divided into four groups (A1C ≤6.5% [N = 109]; >6.5–8% [N = 202]; >8–10% [N = 91]; >10% [N = 47]) and compared with age-, sex-, and BMI-matched nondiabetic control subjects (N = 888). Individuals with A1C values between 6.5 and 8% had a hospital length of stay (LOS) similar to the matched control group (P = 0.5). However, in individuals with A1C values ≤6.5 or >8%, the hospital LOS was significantly longer compared with the control group (P < 0.05). Multivariate regression analysis demonstrated that a higher A1C value was associated with increased hospital LOS after adjustments for age, sex, BMI, race, type of surgery, Charlson Comordity Index, smoking status, and glucose level on the day of surgery (P = 0.02). There were too few events to meaningfully evaluate for death, infections, or readmission rate. CONCLUSIONS Our study suggests that chronic hyperglycemia (A1C >8%) is associated with poor surgical outcomes (longer hospital LOS). Providing a preoperative intervention to improve glycemic control in individuals with A1C values >8% may improve surgical outcomes, but prospective studies are needed.

While hyperglycemia is central to the pathogenesis and management of diabetes mellitus, hypoglycemia and glucose variability also contribute to outcomes. We previously reported on the relationship of glycemic control to outcomes in a large population of diabetic end-stage renal disease (ESRD) patients. Recognizing that ESRD is a risk factor for severe hypoglycemia, we have now analyzed the association between glycosylated hemoglobin A1c (HgbA1c) levels and glycemic variability in those with hypoglycemia. This is a retrospective study of patients with diabetes enrolled in a large hemodialysis program. Hypoglycemia was identified from hospital discharge diagnostic codes. Glycemic variability was assessed by the standard deviation of HgbA1c and glucose levels over time. Hypoglycemia as a discharge diagnosis was documented in 4.1% of patients. Higher baseline HgbA1c was associated with greater risk for hypoglycemia hospitalization, a finding confirmed by time-lagged HgbA1c levels drawn a quarter earlier. Higher baseline HgbA1c categories were also associated with greater variability in HgbA1c levels during the analysis period. Similarly, greater glucose variability was associated with higher mean glucose levels by trend analysis. High, not low, HgbA1c levels are associated with greater risk of severe hypoglycemia, which may derive from glucose variability in the setting of treatment for hyperglycemia. High HgbA1c and glycemic variability are associated with increased risk of hypoglycemia in individuals with diabetes and ESRD.

ObjectivePostoperative hyperglycemia is associated with poor clinical outcomes in patients undergoing cardiac surgery. However, some experts consider hyperglycemia to be an epiphenomenon related to acute stress. We investigated whether preoperative patient characteristics can predict hyperglycemia after cardiac surgery in nondiabetic patients.MethodsThis is a retrospective study of nondiabetic patients undergoing cardiac surgery at a single center during the years 2004 to 2009. Hyperglycemia was defined as 2 consecutive blood glucose readings of 150 mg/dL or greater during the 72 hours after cardiac surgery.ResultsThis study included 1453 patients with hyperglycemia and 2205 patients without hyperglycemia. Hyperglycemic patients were older, were more likely to be men, had higher body mass index, were more likely to be hypertensive and hypercholesterolemic, and had lower left ventricular ejection fractions; in addition, a greater proportion had a history of cardiovascular disease and renal failure. Multivariate logistic regression analysis showed age, gender, body mass index, preoperative serum creatinine, left ventricular ejection fraction, previous cardiac surgery, and preoperative cardiogenic shock to be independently associated with hyperglycemia (P

OBJECTIVE Hypoglycemia is associated with increased mortality in hospitalized patients. We investigated the relationship between spontaneous hypoglycemia versus insulin-associated hypoglycemia and mortality in hospitalized patients. RESEARCH DESIGN AND METHODS Data for this retrospective cohort study were obtained from electronic databases of patients admitted between 1 April 2008 and 30 November 2010. Patients with one or more blood glucose values ≤50 mg/dL on point-of-care glucose testing were considered hypoglycemic. Patients treated with insulin were assumed to have insulin-associated hypoglycemia. Age-, sex-, and race-matched patients with all blood glucose values >70 mg/dL were selected as controls. The Charlson comorbidity index (CCI) was used to control for severity of illness. RESULTS There were four groups: 1) noninsulin-treated hypoglycemia (NTH) (n = 135), 2) insulin-treated hypoglycemia (ITH) (n = 961), 3) noninsulin-treated control (NTC) (n = 1,058), and 4) insulin-treated control (ITC) (n = 736). Mortality was higher in the ITH group compared with the ITC group (20.3 vs. 4.5%, P < 0.0001), with a relatively higher CCI (1.8 vs. 1.5%, P < 0.0001), but much higher in the NTH group compared with the NTC group (34.5 vs. 1.1%, P < 0.0001), with much higher CCI (2.4 vs. 1.1%, P < 0.0001). Mortality was higher in the NTH group compared with the ITH group (P < 0.0001) but lower in the NTC group compared with the ITC group (P < 0.0001). After controlling for age, sex, CCI, and admission to the intensive care unit, insulin treatment was associated with a lower mortality among the hypoglycemic patients; hazard ratio of death in the ITH group relative to the NTH group was 0.34 (95% CI 0.25–0.47, P < 0.0001). CONCLUSIONS Insulin-associated and spontaneous hypoglycemia are associated with increased mortality among hospitalized patients.

Objective To evaluate whether saxagliptin is non-inferior to basal-bolus insulin therapy for glycemic control in patients with controlled type 2 diabetes mellitus (T2DM) admitted to hospital with non-critical illnesses. Research design and methods This was an open-label, randomized controlled clinical trial. Patients received either saxagliptin or basal-bolus insulin, both with correctional insulin doses. The main study outcome was the mean daily blood glucose (BG) after the first day of randomization. Results Of 66 patients completing the study, 33 (age 69±10 years, 40% men) were randomized to saxagliptin and 33 (age 67±10 years, 52% men) to basal-bolus insulin therapy. The mean daily BG was 149.8±22.0 mg/dL in the saxagliptin group and 146.9±30.5 mg/dL in the insulin group (p=0.59). With an observed group difference of 2.9 mg/dL and an a priori margin of 20 mg/dL, inferiority of saxagliptin was rejected in favor of non-inferiority (p=0.007). There was no significant difference in the percentage of high or low BG values. The insulin group received a higher number of insulin injections (2.3±1.7/day vs 1.2±1.9/day; p

ObjectiveWomen with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD) as compared to women without diabetes. We hypothesized that bone strength is diminished in women with T2DM after accounting for lean body mass, which may contribute to their increased fracture risk.MethodsParticipants from Women's Health Initiative Observational Study were included in this cross-sectional study. These analyses include 3 groups of women: 1) T2DM women on diet or oral hypoglycemic agents (n=299); 2) T2DM women on insulin therapy (with or without oral agents) (n=128); and 3) Non-diabetic control women (n=5497). Hip structural analyses were done using the validated Beck's method on hip scans from dual energy x-ray absorptiometry (DXA). We compared BMD and section modulus (bending strength) at the narrow neck with and without correcting for total body DXA lean body mass.ResultsWomen in all three groups were of similar ages (63.7, 64.6 and 64.2 years, respectively) and heights, but those with T2DM were heavier, with greater lean body weight vs controls (P

Recent data suggest that mineralocorticoid receptor activation can affect insulin resistance independent of its effects on blood pressure. This review discusses new evidence linking mineralocorticoid receptor to insulin resistance and the underlying mechanisms of these effects.Observational studies have shown mineralocorticoid activity to be associated with insulin resistance irrespective of race, blood pressure or body weight. Increased mineralocorticoid activity may be the common link between obesity, hypertension, dyslipidemia and insulin resistance, features that make up the metabolic syndrome. Treatment of primary aldosteronism is associated with a decrease in insulin resistance and provides one of the most convincing evidences in favor of the contribution of mineralocorticoid receptor to insulin resistance. Dietary salt restriction, which increases aldosterone levels, is also associated with an increase in insulin resistance. Potential mechanisms by which mineralocorticoid receptor may contribute to insulin resistance include a decreased transcription of the insulin receptor gene, increased degradation of insulin receptor substrates, interference with insulin signaling mechanisms, decreased adiponectin production and increased oxidative stress and inflammation. Advantages of mineralocorticoid receptor antagonists on insulin resistance have been demonstrated in animal models.There may be a benefit of mineralocorticoid receptor antagonists in human insulin resistance states, but more clinical research is needed to explore these possibilities.

Low-salt (LS) diet activates the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which can increase insulin resistance (IR). We investigated the hypothesis that LS diet is associated with an increase in IR in healthy subjects. Healthy individuals were studied after 7 days of LS diet (urine sodium20 mmol/d) and 7 days of high-salt (HS) diet (urine sodium150 mmol/d) in a random order. Insulin resistance was measured after each diet and compared statistically, unadjusted and adjusted for important covariates. One hundred fifty-two healthy men and women, aged 39.1 ± 12.5 years (range, 18-65) and with body mass index of 25.3 ± 4.0 kg/m(2), were included in this study. Mean (SD) homeostasis model assessment index was significantly higher on LS compared with HS diet (2.8 ± 1.6 vs 2.4 ± 1.7, P.01). Serum aldosterone (21.0 ± 14.3 vs 3.4 ± 1.5 ng/dL, P.001), 24-hour urine aldosterone (63.0 ± 34.0 vs 9.5 ± 6.5 μg/d, P.001), and 24-hour urine norepinephrine excretion (78.0 ± 36.7 vs 67.9 ± 39.8 μg/d, P.05) were higher on LS diet compared with HS diet. Low-salt diet was significantly associated with higher homeostasis model assessment index independent of age, sex, blood pressure, body mass index, serum sodium and potassium, serum angiotensin II, plasma renin activity, serum and urine aldosterone, and urine epinephrine and norepinephrine. Low-salt diet is associated with an increase in IR. The impact of our findings on the pathogenesis of diabetes and cardiovascular disease needs further investigation.

OBJECTIVE Cases of acute pancreatitis have been reported in association with exenatide, sitagliptin, and type 2 diabetes without use of these medications. It remains unknown whether exenatide or sitagliptin increase the risk of acute pancreatitis. RESEARCH DESIGN AND METHODS A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 786,656 patients were analyzed. Cox proportional hazard models were built to compare the risk of acute pancreatitis between diabetic and nondiabetic subjects and between exenatide, sitagliptin, and control diabetes medication use. RESULTS Incidence of acute pancreatitis in the nondiabetic control group, diabetic control group, exenatide group, and sitagliptin group was 1.9, 5.6, 5.7, and 5.6 cases per 1,000 patient years, respectively. The risk of acute pancreatitis was significantly higher in the combined diabetic groups than in the nondiabetic control group (adjusted hazard ratio 2.1 [95% CI 1.7–2.5]). Risk of acute pancreatitis was similar in the exenatide versus diabetic control group (0.9 [0.6–1.5]) and sitagliptin versus diabetic control group (1.0 [0.7–1.3]). CONCLUSIONS Our study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but did not find an association between the use of exenatide or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk.

Context: Aldosterone production is associated with insulin resistance in obese and hypertensive subjects. However, its effect on insulin sensitivity in healthy subjects is not clear. Objective: The objective of this study was to test the hypothesis that increased aldosterone production is associated with lower insulin sensitivity in healthy subjects. Design: This is an analysis of data previously collected during studies conducted as part of the International Hypertensive Pathotype Consortium. Participants and Interventions: Eighty-four subjects free of any medical or psychiatric illness were included in this study. They were studied after 7 d of a standardized high-sodium diet confirmed by 24-h urine sodium above 200 mEq. Insulin sensitivity index (ISI) was calculated after a 75-g oral glucose load with glucose and insulin measurements at 0, 30, 60, and 120 min. Serum aldosterone levels were measured after 45 min of angiotensin II (3 ng/kg/min) infusion. Results: There were significant negative correlations between ISI and age, body mass index (BMI), diastolic blood pressure, and angiotensin II-stimulated aldosterone level (P < 0.01). On multivariate regression analysis, stimulated aldosterone level was an independent predictor of ISI after adjusting for age, BMI, and diastolic blood pressure. Stimulated aldosterone level predicted 8% of the variance in ISI (P = 0.003) with age, BMI, and diastolic blood pressure together predicting 23% of the variance in ISI. Thus, the final regression model predicted 31% of the variance in ISI (P < 0.0001). Conclusions: Aldosterone production is associated with insulin resistance in normotensive healthy subjects independent of traditional risk factors.

Context: The mechanisms underlying obesity-mediated cardiovascular disease are not fully understood. Aldosterone and insulin resistance both are associated with obesity and cardiovascular disease. Objectives: The objectives of this study were to test the hypotheses that aldosterone production is elevated and associated with insulin resistance in overweight adults on a high-sodium diet. Participants/Interventions: Healthy normotensive adults were categorized as lean body mass index (BMI) less than 25 kg/m2 (n = 63) or overweight BMI 25 kg/m2 or greater (n = 57). After 7 d of a high-sodium diet, participants fasted overnight and remained supine throughout hemodynamic and laboratory assessments and angiotensin II (AngII) stimulation. Results: The overweight group, compared with the lean group, had higher 24-h urinary aldosterone (9.0 ± 0.8 vs. 6.6 ± 0.5 μg per 24 h; P = 0.003) and higher AngII-stimulated serum aldosterone (11.4 ± 1.0 vs. 9.0 ± 0.6 ng/dl; P = 0.04). There were no differences in 24-h urinary cortisol or sodium or supine measurements of plasma renin activity, serum aldosterone, or serum potassium. The homeostasis model assessment of insulin resistance was predicted by urinary aldosterone excretion (r = 0.32, P = 0.03) and serum aldosterone response to AngII stimulation (r = 0.28, P = 0.02) independent of age and BMI. Conclusion: Urinary aldosterone excretion and AngII-stimulated aldosterone are increased in overweight, compared with lean, normotensive adults. The correlation of these measures of aldosterone production with insulin resistance suggests a potential role for aldosterone in the pathophysiology of obesity-mediated insulin resistance.

Preclinical studies have convincingly demonstrated a role for the mineralocorticoid receptor (MR) in adipose tissue physiology. These studies show that increased MR activation causes adipocyte dysfunction leading to decreased production of insulin-sensitizing products and increased production of inflammatory factors, creating an environment conducive to metabolic and cardiovascular disease. Accumulating data also suggest that MR activation may be an important link between obesity and metabolic syndrome. Moreover, MR activation may mediate the pathogenic consequences of metabolic syndrome. Recent attempts at reversing cardiometabolic damage in patients with type 2 diabetes using MR antagonists have shown promising results. MR antagonists are already used to treat heart failure where their use decreases mortality and morbidity over and above the use of traditional therapies alone. However, more data are needed to establish the benefits of MR antagonists in diabetes, obesity, and metabolic syndrome.

Received June 28, 2004; revision received August 26, 2004; accepted October 15, 2004. The original description of the metabolic syndrome by Reaven1 consisted of obesity, insulin resistance, hypertension, impaired glucose tolerance or diabetes, hyperinsulinemia and dyslipidemia characterized by elevated triglyceride, and low HDL concentrations. All of the features described above are risk factors for atherosclerosis, and thus, metabolic syndrome constituted a significant risk for coronary heart disease2–5 (Table). The features of obesity/overweight and insulin resistance also provided a significant risk for developing type 2 diabetes.5,6 The risks for coronary heart disease and diabetes with metabolic syndrome are greater than those for simple obesity alone, and therefore, an understanding of the pathogenesis and through it, a rational approach to its therapy are of prime importance. View this table: Classic Biological Effects of Insulin and Classic Metabolic Syndrome Based on Resistance to the Metabolic Effects of Insulin As our understanding of the action of insulin evolves to comprehensively include the recent discoveries,7 we can better see that insulin resistance is the basis of most if not all of the features of this syndrome. The original conceptualization of this syndrome was on the basis of resistance to the metabolic actions of insulin. Thus, hyperinsulinemia, glucose intolerance, type 2 diabetes, hypertriglyceridemia, and low HDL concentrations could be accounted for by resistance to the actions of insulin on carbohydrate and lipid metabolism. Although the features described above would to some extent explain the atherogenesis, Reaven has maintained that hyperinsulinemia itself contributes to atherogenicity, and thus, insulin is atherogenic, leading to the coronary heart disease and cerebrovascular disease associated with this syndrome. Obesity probably leads to hypertension through (1) increased vascular tone created by a reduced bioavailability of NO because of increased oxidative stress,8 (2) increased asymmetric dimethylarginine (ADMA) concentrations,9 (3) increased sympathetic …

In view of the pro-oxidant and proinflammatory effects of angiotensin II, we have tested the hypothesis that valsartan, an angiotensin receptor blocker, may exert a suppressive action on reactive oxygen species (ROS) generation, nuclear factor kappa B (NF-kappa B) in mononuclear cells. Four groups of eight normal subjects were given 1) 160 mg daily of valsartan, 2) 80 mg daily of simvastatin, 3) 40 mg quinapril, or 4) no treatment. Fasting blood samples were obtained before treatment and at d 1, 8, and 14 (7 d after the cessation of the drug). After valsartan, ROS generation by polymorphonuclear cells and mononuclear cells fell significantly by more than 40% (P0.01). NF-kappa B binding activity and the expression of total cellular p65, a protein component of NF-kappa B, fell significantly (P0.01). The expression of inhibitor kappa B (I kappa B) increased significantly (P0.05). Plasma C-reactive protein (CRP) concentration fell significantly (P0.01). All indices, except I kappa B, reverted toward baseline, 7 d after the cessation of the drug. I kappa B persisted in an elevated state. Neither quinapril nor simvastatin given for 7 d produced a suppression of ROS generation, intranuclear NF-kappa B, p65, or CRP, and these two agents did not alter cellular I kappa B either. The untreated controls also did not demonstrate a change in their ROS generation or NF-kappa B binding activity or plasma CRP concentration. We conclude that valsartan at a modest dose exerts a profound and rapid ROS and inflammation-suppressive effect that may be relevant to its potential beneficial effects in atherosclerosis, diabetes, and congestive cardiac failure. In contrast, quinapril and simvastatin produced no similar effect over the period of 1 wk. Our observations may also have implications to clinical situations in which a rapid antiinflammatory effect is required.

The objective of this study was to evaluate the gonadal function in men with type 2 diabetes with erectile dysfunction.We examine records of 50 patients with type 2 diabetes and erectile dysfunction who had low free testosterone concentrations. All patients had plasma concentrations of luteinizing hormones (LH), follicle-stimulating hormone (FSH), and prolactin measured.Of the 50 patients with low free testosterone concentrations (0.97 +/- 0.4 ng/dL; reference range, 1.30-3.10), 43 had normal (inappropriately low) LH (5.9 +/- 2.9 mIU/mL), FSH (5.6 +/- 2.4 mIU/mL), and testosterone concentrations, five had elevated LH, FSH concentrations (Hypogonadotropic hypogonadism), and two had prolactinoma. Patients with hypogonadotropic hypogonadism were in their mid 50's and had experienced a decline in their testosterone levels much earlier than that expected from the normal age-related decline. Although a majority of the patients were obese, there was no relationship between testosterone (free or total) and BMI, between testosterone and HbA(1c), duration of diabetes or the age of the patient. Patients given testosterone supplementation experienced a subjective improvement in their wellbeing, but reported no significant improvement in their erectile dysfunction.We conclude that patients with erectile dysfunction require careful assessment and that the most frequent gonadal defect in these patients is that of hypogonadotropic hypogonadism, a defect not previously associated with type 2 diabetes. The mechanism underlying this defect requires investigation. The value of testosterone replacement in such patients needs to be assessed critically.

BACKGROUND It was recently shown that glucose challenge leads to increased generation of reactive oxygen species (ROS) by polymorphonuclear leukocytes (PMNs) and mononuclear cells (MNCs). OBJECTIVE To further elucidate the relation between nutrition and ROS generation, we investigated the effect of lipid and protein challenges on ROS generation by leukocytes. DESIGN After having fasted overnight, one group of healthy subjects consumed a carbohydrate- and protein-free cream preparation (1257 kJ) and another group of healthy subjects consumed an equienergetic pure preparation of casein. Sequential blood samples were obtained after the intake of cream and casein. ROS were measured by chemiluminescence after stimulation by N-formyl-methionyl-leucinyl-phenylalanine. Lipid peroxidation was measured as thiobarbituric acid-reactive substances (TBARS) and alpha-tocopherol was measured by HPLC. RESULTS ROS generation by MNCs and PMNs increased significantly 1, 2, and 3 h after cream intake and 1 h after protein intake. Cholesterol concentrations did not change significantly, whereas triacylglycerol concentrations increased significantly 2 h after cream intake. Total TBARS concentrations increased 1 h after cream intake and remained elevated 3 h after intake, but the increase was not significant when corrected for changes in triacylglycerol. After casein intake, total cholesterol, triacylglycerol, and TBARS concentrations did not change significantly. alpha-Tocopherol concentrations did not change significantly after either cream or casein intake. CONCLUSIONS Both fat and protein intakes stimulate ROS generation. The increase in ROS generation lasted 3 h after cream intake and 1 h after protein intake. Cream intake also caused a significant and prolonged increase in lipid peroxidation. These data are important because increased ROS generation and lipid peroxidation are key events in atherogenesis.

We appreciate Dr. Dhatariya’s comments (1) and are glad to know that the Joint British Diabetes Societies have developed guidelines for optimal A1C levels before surgery. We were not aware of these guidelines and believe that most surgeons and anesthesiologists in the U.S. are not aware of them either. In our opinion, the literature to date has focused on perioperative glycemic control—on the day of …

We have recently demonstrated that troglitazone exerts an anti-inflammatory effect in the insulin resistant obese in vivo in parallel with its insulin-sensitizing effect. Because these effects are thought to be mediated through peroxisome proliferator-activated receptors α and γ (PPARα and PPARγ), we have now examined the possibility that troglitazone may modulate the expression of PPARα and PPARγ. Seven obese hyperinsulinemic subjects were administered 400 mg troglitazone daily for 4 weeks. Fasting blood samples were obtained before and during troglitazone therapy at 1, 2, and 4 weeks. Fasting insulin concentrations fell at week 1 and persisted at lower levels till 4 weeks. PPARγ expression fell significantly at week 1 and fell further at weeks 2 and 4. In contrast, PPARα expression increased significantly at week 2 and further at week 4. 9- and 13-hydroxyoctadecanoic acid, products of linoleic acid peroxidation and agonists of PPARγ, decreased during troglitazone therapy. We conclude that troglitazone, ...

It has been shown recently that troglitazone exerts an anti-inflammatory effect, in vitro, and in experimental animals. To test these properties in humans, we investigated the effect of troglitazone on the proinflammatory transcription factor nuclear factor-κB and its inhibitory protein IκB in mononuclear cells (MNC) and plasma soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and C-reactive protein. We also examined the effect of troglitazone on reactive oxygen species generation, p47phox subunit expression, 9-hydroxyoctadecadienoic acid (9-HODE), 13-HODE, o-tyrosine, and m-tyrosine in obese patients with type 2 diabetes. Seven obese patients with type 2 diabetes were treated with troglitazone (400 mg/day) for 4 weeks. Blood samples were obtained at weekly intervals. Nuclear factor-κB binding activity in MNC nuclear extracts was significantly inhibited after troglitazone treatment at week 1 and continued to be inhibited up to week 4. On the ...

Since glucose intake acutely increases reactive oxygen species (ROS) generation by polymorphonuclear leucocytes (PMN) and mononuclear cells (MNC), we have now investigated whether a fast over a period of 48h reduces ROS generation by these cells. Eight normal subjects were fasted for 48h. Blood samples were obtained at 0, 24h and 48h. ROS generation by PMN fell significantly at 24h (66.1 ± 19.5% of basal) and further at 48h (45.9 ± 23.0 % of basal; p < 0.001). ROS generation by MNC fell to 62.4 ± 16.5% at 24h and by 48.4 ± 16.5% (p < 0.001) by 48h. The level of p47phox subunit, an index of NADPH oxidase, the enzyme converting molecular oxygen to superoxide (O˙2−) radical, also fell in parallel. Plasma o-tyrosine/phenylalanine ratio fell significantly from 0.326 ± 0.053 mmol/mol to 0.303 ± 0.055 mmol/mol at 48h and m-tyrosine/phenylalanine ratio fell from 0.363 ± 0.063 mmol/mol to 0.340 ± 0.064 mmol/mol (p < 0.05). Thus, a 48h fast may reduce ROS generation, total oxidative load and oxidative dama...