Decreased adiponectin links elevated adipose tissue autophagy with adipocyte endocrine dysfunction in obesity.

BACKGROUND/OBJECTIVES: Adipose tissue (AT) autophagy gene expression is elevated in human obesity, correlating with increased metabolic risk, but mechanistic links between the two remain unclear. Thus, the objective of this study was to assess whether elevated autophagy may cause AT endocrine dysfunction, emphasizing the putative role of adiponectin in fat-liver endocrine communication. SUBJECTS/METHODS: We utilized a large (N=186) human AT biobank to assess clinical associations between human visceral AT autophagy genes, adiponectin and leptin, by multivariate models. A broader view of adipocytokines association with elevated autophagy was assessed using adipocytokine array. Finally, to establish causality, ex vivo studies utilizing a murine AT-hepatocyte cell line co-culture system was used. RESULTS: Circulating high-molecular-weight adiponectin and leptin levels were associated with human omental-AT expression of ATG5 mRNA, associations that remained significant (ß=-0.197, P=0.011; ß=0.267, P<0.001, respectively) in a multivariate model adjusted for age, sex, body mass index and interleukin-6 (IL-6). A similar association was observed with omental-AT LC3A mRNA levels. Bafilomycin-A1 (Baf A) pretreatment of AT explants from high-fat-fed (HFF) mice had no effect on the secretion of some AT-derived endocrine factors, but partially or fully reversed obesity-related changes in secretion of a subset of adipocytokines by >30%, including the obesity-associated upregulation of IL-6, vascular endothelial growth factor, tumor necrosis factor alpha (TNFα) and certain insulin-like growth factor-binding proteins, and the HFF-induced downregulated secretion of IL-10 and adiponectin. Similarly, decreased adiponectin and increased leptin secretion from cultured adipocytes stimulated with TNFα+IL-1ß was partially reversed by small interfering RNA-mediated knockdown of ATG7. AT explants from HFF mice co-cultured with Hepa1c hepatoma cells impaired insulin-induced Akt and GSK3 phosphorylation. This effect was significantly reversed by pretreating explants with Baf A, but not if adiponectin was immunodepleted from the conditioned media. CONCLUSIONS: Reduced secretion of adiponectin may link obesity-associated elevated AT autophagy/lysosomal activity with adipose endocrine dysfunction.

Hidradenitis suppurativa and metabolic syndrome: a comparative cross-sectional study of 3207 patients.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease. OBJECTIVES: To evaluate the association between HS and metabolic syndrome and its component morbidities in a large, community-based cohort of patients with HS, using the database of Clalit Health Services, the largest public healthcare provider in Israel. METHODS: A cross-sectional study was performed. Metabolic syndrome was defined as the presence of at least three of the following conditions: diabetes, hyperlipidaemia, hypertension and obesity. The association between HS and metabolic syndrome was assessed by a multivariate logistic regression model, adjusting for age, sex, diabetes, hypertension, hyperlipidaemia, obesity and smoking status. RESULTS: The study included 3207 patients with HS (general frequency of 0·07%) diagnosed by a dermatologist in primary-care centres, and 6412 age- and sex-matched control patients without HS. HS was significantly associated with metabolic syndrome [odds ratio (OR) 1·61, 95% confidence interval (CI) 1·36-1·89], diabetes (OR 1·41, 95% CI 1·19-1·66), obesity (OR 1·71, 95% CI 1·53-1·91), hyperlipidaemia (OR 1·14, 95% CI 1·02-1·28) and hypertension (OR 1·19, 95% CI 1·03-1·38). CONCLUSIONS: We found an association between HS and diabetes, hyperlipidaemia, obesity, hypertension and metabolic syndrome among a large community-based cohort of patients with HS. Clinicians should take into account that patients with HS may have one or more undiagnosed components of metabolic syndrome despite their young age. Thus, appropriate targeted screening is advised.

The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan: a randomised trial.

AIMS: To compare the incidence of symptomatic hypoglycaemia in fasting Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan. METHODS: Patients with type 2 diabetes (age ≥ 18 years) who were treated with a stable dose of a sulphonylurea with or without metformin for at least 3 months prior to screening, who had an HbA(1c) < 10% and who expressed their intention to daytime fast during Ramadan were eligible for this open-label study. Patients were randomised in a 1 : 1 ratio to either switch to sitagliptin 100 mg qd or to remain on their prestudy sulphonylurea. Patients completed daily diary cards to document information on hypoglycaemic symptoms and complications. The primary end-point was the overall incidence of symptomatic hypoglycaemia recorded during Ramadan. RESULTS: Of the 1066 patients randomised, 1021 (n = 507 for sitagliptin and n = 514 for sulphonylurea) returned at least one completed diary card and were included in the analysis. The proportion of patients who recorded one or more symptomatic hypoglycaemic events during Ramadan was lower in the sitagliptin group (6.7%) compared with the sulphonylurea group (13.2%). The risk of symptomatic hypoglycaemia was significantly decreased with sitagliptin relative to sulphonylurea treatment (Mantel-Haenszel relative risk ratio [95% CI] = 0.51 [0.34, 0.75]; p < 0.001). There were no reported events that required medical assistance (i.e. visits to physician or emergency room or hospitalisations) or were considered severe (i.e. events that caused loss of consciousness, seizure, coma or physical injury) during Ramadan. CONCLUSIONS: In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptin-based regimen decreased the risk of hypoglycaemia compared with remaining on a sulphonylurea-based regimen. The incidence of hypoglycaemia was lower with gliclazide relative to the other sulphonylurea agents and similar to that observed with sitagliptin.

Depressive symptoms and risk for malnutrition among hospitalized elderly people.

OBJECTIVES: To explore the association between depressive symptoms and risk for malnutrition in hospitalized elderly people. METHODS: 195 hospitalized medical patients older than 65 years of age were studied in a cross-sectional design. Depression was assessed by 30-item Geriatric Depression Scale (GDS), nutritional status was evaluated by the Mini-Nutritional Assessment (MNA). Eating and digestive problems were assessed using selected items of Nutrition Risk Index (NRI), cognitive and functional status by Folstein and Barthel indices respectively; demographic data, diagnoses and medications were obtained from medical records. RESULTS: The prevalence of depression in the studied population was 28%. MNA scores were significantly lower among depressed patients as compared with non-depressed (22.86 vs. 24.96, p < 0.001), indicating a higher risk for undernutrition among depressed persons. After controlling for age, cognitive status, functional ability, and number of illnesses, undernutrition was significantly associated with depression (OR = 2.23; 95% CI: 1.04-4.8). CONCLUSIONS: Nutritional risk is associated with depression in aged inpatients. Close case management of the elderly hospitalized patients that include assessment and treatment for both disorders may be beneficial.

Mixing of nasopharyngeal and oropharyngeal samples to identify potential respiratory pathogens in adults.

A mixed culture of oropharyngeal swabs, nasopharyngeal swabs and nasopharyngeal washings, taken from 400 patients, was compared to separate cultures of the same samples. The mixed culture identified Streptococcus pneumoniae in 37 of 40 (93%) patients with positive samples, Hemophilus influenzae in 28 of 29 (97%), and Moraxella catarrhalis in 94 of 94 (100%). These sensitivity rates clearly justify the use of mixed cultures instead of separate cultures for clinical and epidemiological purposes. The reduction in costs stemming from the use of mixed cultures may have a decisive influence when considering this test for extensive clinical and epidemiological purposes.

Increased red cell aggregation is correlated with HbA1C and lipid levels in type 1 but not type 2 diabetes.

The present study was designed to study RBC aggregability in type 1 and type 2 DM by a new method based on the dielectric properties of disperse systems. This dielectric method has a significantly higher sensitivity to detect enhanced RBC aggregation in DM than other methods. Aggregability is increased in type 1 DM and even more markedly in type 2 diabetic patients. The enhanced RBC aggregation in type 1 diabetes was significantly correlated with the levels of HbA(1C), cholesterol and triglycerides. However, no correlation between metabolic control and RBC aggregability was found in type 2 DM. The in vitro addition of non-toxic, low molecular weight dextran improves the high RBC aggregation in diabetes type 2. In the future, low molecular weight dextran may be used in DM patients clinically to lower the risk for vascular complications, after the problem of filtration is solved.

[Trends and characteristics of diabetes-related lower limb amputations in the Negev, 1996-1999].

BACKGROUND: The loss of a lower limb because of diabetic foot problems such as infections is an important complication of diabetes mellitus. The goals of this study were: (1) to examine trends in incidence of diabetic-related lower limb amputations in the Negev, (2) to describe the clinical characteristics of patients who underwent amputations in the Soroka University Medical Center and (3) to estimate in-hospital mortality and its predictors. METHODS: This study included all diabetic patients who underwent non-traumatic lower limb amputation in the Soroka Hospital during the period 1996-1999. The computerized hospitalization files and surgery logs during the study period were reviewed for ICD-9 diagnoses of diabetes and amputations. For each patient, hospitalization records were abstracted and data on socio-demographic and clinical characteristics were collected. RESULTS: During the study period 411 amputations were performed on 250 diabetic patients (1.6 amputation/person). The estimated mean annual incidence rate of lower limb amputations in the Negev was 5 per 1000 diabetic patients, 27.3 per 100,000 total population, and 45 per 100,000 adults above 18 years of age. The mean age was 68 (SD +/- 11.4) years. The most frequent types of surgery were standard below-knee amputation. Fourteen percent of patients died during hospitalization. Systolic blood pressure, white blood count and serum creatinine at admission were independent predictors of in-hospital mortality. CONCLUSIONS: The incidence of lower limb amputation in the Negev is similar to that reported in other countries. Interventions directed to early detection of diabetic foot problems may have an impact on the reduction of lower limb amputations and related mortality.

Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patients.

AIMS: To compare the efficacy of insulin pump treatment with multiple daily injections in the treatment of poorly controlled obese Type 2 diabetic patients already receiving two or more daily injections of insulin plus metformin. METHODS: Forty obese Type 2 diabetic subjects (using insulin) were randomized to treatment with continuous subcutaneous infusion pump (CSII) (Minimed) or multiple daily insulin injections (MDI). At the end of the first 18-week treatment period, patients underwent a 12-week washout period during which they were treated with MDI plus metformin. They were then crossed-over to the other treatment for an 18-week follow-up period. Patients performed 4-point daily self blood-glucose monitoring (SBGM) on a regular basis and 7-point monitoring prior to visits 2, 8, 10 and 16. A subset of patients underwent continuous glucose monitoring using the Minimed(R) continuous glucose monitoring system (CGMS) at visits 2, 8, 10 and 16. A standard meal test was performed in which serum glucose was tested at fasting and once each hour for 6 h following a test meal. Glucose levels were plotted against time and the area under the curve (AUC) was calculated. HbA(1c), weight, daily insulin dose and hypoglycaemic episodes were recorded. RESULTS: In obese Type 2 diabetic patients already treated with insulin, treatment with CSII significantly reduced HbA(1c) levels compared with treatment with MDI. An additional CSII treatment benefit was demonstrated by reduced meal-test glucose AUC. Initial reduction of daily insulin requirement observed in CSII-treated subjects during the first treatment period was attributable to a period effect and did not persist over time. CONCLUSIONS: In the intent-to-treat analysis, CSII appeared to be superior to MDI in reducing HbA(1c) and glucose AUC values without significant change in weight or insulin dose in obese, uncontrolled, insulin-treated Type 2 diabetic subjects.

The patient with unstable angina: no evidence of MI.

A 53-year-old type 2 diabetic woman with macrovascular complications as well as the components of the metabolic syndrome presents with an unstable angina and ST depression on electromiogram. The negative impact of female gender, microvascular complications, and metabolic parameters on cardiovascular risk and prognosis, are emphasized. The lack of evidence for hormone replacement, antioxidant or universal folic acid therapy is underscored. Treatment options including PTCA and stenting augmented with low molecular weight heparin, clopidrogel and IIb/IIIa antagonists as well as optimal metabolic control are discussed.

The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes.

HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 micromol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 micromol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipolysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients.

[Prevalence of fibromyalgia in type 2 diabetes mellitus].

This study aimed to assess the prevalence of fibromyalgia and other pain characteristics among patients with type 2 diabetes mellitus. We assessed 137 patients with type 2 diabetes mellitus and a control group of 139 patients matched for age and sex that do not suffer from diabetes mellitus. We examined 9 of 18 typical tender points and 4 control points with a dolorimeter. There was no difference in the prevalence of fibromyalgia among men in both groups. However, diabetic men had more tender points than men in the control group and their threshold for pain at the corresponding tender points was significantly lower compared to that of the men in the control group. The diabetic men also reported more pain than patients in the control group. Diabetic women, on the other hand, had a significantly higher prevalence of fibromyalgia than women in the control group: 23.3% versus 10.6% respectively (p = 0.043). There was no significant difference in the number of tender points and the pain threshold in the two groups of women. Diabetic women reported more pain than the women in the control group. In both diabetic men and women the number of tender points and dolorimeter count directly correlated with the duration of diabetes.

Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients.

To evaluate the effect of dietary fiber supplements on levothyroxine (T4) bioavailability in hypothyroid patients, dietary fiber-containing supplementation was withheld from patients requiring disproportionately high doses of T4, in whom a dietary history revealed ingestion of a dietary fiber supplement. The dose of T4 was maintained at a constant level. Serum thyrotropin (TSH) was assessed before and after removal of the dietary fiber supplements. T4 requirements, reflected by either decreased serum TSH or by decreased T4 dose, was observed in conjunction with decreased dietary fiber intake compared with T4 requirement during increased dietary fiber intake. In vitro experiments carried out to determine the mechanism of interaction between dietary fiber and T4 revealed dose dependent, nonspecific adsorption of levothyroxine by wheat bran. These results indicate a decrease in T4 bioavailability by dietary fiber through a mechanism involving nonspecific adsorption of T4 to dietary fibers. Increased intake of dietary fiber may account for the need for larger than expected doses of T4 in some hypothyroid patients.

The risk of developing an acute coronary event as a measure of the quality of triage of patients presenting to the emergency room with chest pain.

The risk of developing an acute coronary event (ACE) in patients presenting to the emergency room with chest pain or shortness of breath was assessed in a prospective blinded fashion. The Time Insensitive Predictive Instrument (TIPI), which is appropriate for both prospective and retrospective assessment, was used to determine the risk. The average predictive probability for developing ACE among the 168 patients examined was 36.5%. The triage process created groups of patients with significantly different relative risks for ACE. The average predictive probability among the patients discharged from the emergency room was 23%, among those hospitalized in internal medicine 44%, and among those hospitalized in the coronary care unit (CCU) 62.4%. Among patients presenting with ACE the predictive probability determined using TIPI was 57.6% compared to 26.3% in patients without ACE. This difference was unaffected by the triage process or the decision where to hospitalize. TIPI permits assessment of the emergency room physician's decisions and also mirrors the limitations of the system as a whole in treating patients referred to the emergency room for a suspected acute coronary event.

Assessment of nonarticular tenderness and prevalence of fibromyalgia in hyperprolactinemic women.

OBJECTIVE: To assess nonarticular tenderness and prevalence of fibromyalgia syndrome (FMS) in hyperprolactinemic subjects. METHODS: Twenty-one consecutive women with hyperprolactinemia (HPRL) and 44 consecutive women with normal prolactin levels (PRL) were examined in the fertility unit by one observer during a 24-month period. Mean age was 31 years, range 22-46 years. Hyperprolactinemia was defined as PRL levels > 24.5 ng/ml (immunoradiometric assay). In all women, a count of 18 tender points (TP) was conducted by thumb palpation. Tenderness of some of the TP sites (9 points) as well as control point sites (4 points) was further assessed using a Chatillon dolorimeter. All women were questioned about the presence of widespread pain or aching. Women were considered to have FMS if they met the American College of Rheumatology (ACR) criteria for diagnosis. RESULTS: Of the 21 women with HPRL, 15 (71%) had FMS vs only 2 of 44 (4.5%) normoprolactinemic women (p < 0.0001). Thresholds of tenderness of 9 fibrositic points were 2.7 (1.5) kg [mean (standard deviation)] for HPRL women vs 5.0 (1.4) (kg) for women with normal PRL (p < 0.0001). Thresholds of tenderness of 4 control points were 5.2 (1.5) (kg) for women with HPRL vs 6.8 (1.1) (kg) for normoprolactinemic women (p < 0.0001). The frequency of FMS was directly associated with the level of PRL. CONCLUSIONS: We suggest that FMS is very common in a subset of women with HPRL and that its frequency is directly associated with the degree of hyperprolactinemia. Women with HPRL have lower thresholds of tenderness than women with normal PRL. More studies are needed to clarify the relationships between PRL, FMS and tenderness.