Alexander Kokkinos

Gut hormones as mediators of appetite and weight loss after roux-en-Y gastric bypass

Objective:To evaluate the physiologic importance of the satiety gut hormones. Background:Controversy surrounds the physiologic role of gut hormones in the control of appetite. Bariatric surgery remains the most effective treatment option for obesity, and gut hormones are implicated in the reduction of appetite and weight after Roux-en-Y gastric bypass. Methods:We correlated peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) changes within the first week after gastric bypass with changes in appetite. We also evaluated the gut hormone responses of patients with good or poor weight loss after gastric bypass. Finally, we inhibited the gut hormone responses in gastric bypass patients and then evaluated appetite and food intake. Results:Postprandial PYY and GLP-1 profiles start rising as early as 2 days after gastric bypass (P < 0.05). Changes in appetite are evident within days after gastric bypass surgery (P < 0.05), and unlike other operations, the reduced appetite continues. However, in patients with poor weight loss after gastric bypass associated with increased appetite, the postprandial PYY and GLP-1 responses are attenuated compared with patients with good weight loss (P < 0.05). Inhibiting gut hormone responses, including PYY and GLP-1 after gastric bypass, results in return of appetite and increased food intake (P < 0.05). Conclusion:The attenuated appetite after gastric bypass is associated with elevated PYY and GLP-1 concentrations, and appetite returns when the release of gut hormones is inhibited. The results suggest a role for gut hormones in the mechanism of weight loss after gastric bypass and may have implications for the treatment of obesity.

Eating Slowly Increases the Postprandial Response of the Anorexigenic Gut Hormones, Peptide YY and Glucagon-Like Peptide-1

CONTEXT The rate at which people eat has been suggested to be positively associated with obesity, although appetite and related gut hormones have not been measured. The objective of the study was to determine whether eating the same meal at varying speeds elicits different postprandial gut peptide responses. DESIGN AND SETTING This was a crossover study at a clinical research facility. STUDY PARTICIPANTS Seventeen healthy adult male volunteers participated in the study. INTERVENTION A test meal consisting of 300 ml ice cream (675 kcal) was consumed in random order on two different sessions by each subject: meal duration took either 5 or 30 min. MAIN OUTCOME MEASURES The postprandial response of the orexigenic hormone ghrelin and the anorexigenic peptides peptide YY and glucagon-like peptide-1 over 210 min was assessed. Visual analog scales for the subjective feelings of hunger and fullness were completed throughout each session. RESULTS Peptide YY area under the curve (AUC) was higher after the 30-min meal than after the 5-min meal (mean +/- sem AUC 5 min meal: 4133 +/- 324, AUC 30 min meal: 5250 +/- 330 pmol/liter . min, P = 0.004), as was glucagon-like peptide-1 AUC (mean +/- sem AUC 5 min meal: 6219 +/- 256, AUC 30 min meal: 8794 +/- 656 pmol/liter . min, P = 0.001). There was a trend for higher visual analog scale fullness ratings immediately after the end of the 30-min meal compared with immediately after the 5-min meal. There were no differences in ghrelin response. CONCLUSIONS Eating at a physiologically moderate pace leads to a more pronounced anorexigenic gut peptide response than eating very fast.

Successful treatment of refractory adult-onset Still’s disease with infliximab. A prospective, non-comparative series of four patients

In this prospective, non-comparative case series, four patients with severe and highly active adult-onset Still’s disease (AOSD), refractory to high doses of corticosteroids (which had been combined with methotrexate in three of them) and methotrexate were treated with infliximab (initial dose 3–5 mg/kg, continuing at intervals depending on the patient’s individual disease activity). Resolution of their symptoms, which was evident within few days after the first infusion, and a parallel rapid improvement of the acute inflammatory response indices were observed in all. Concomitant corticosteroid treatment was reduced after the first courses of treatment with infliximab, which was well tolerated, and complete disease remission was sustained during a 5–18-month follow-up period. Although further studies to confirm long-term efficacy and safety in larger numbers of patients are needed, we suggest that administration of infliximab with observation for objective improvement is the treatment of choice in cases of AOSD refractory to conventional treatment.

Diet-induced thermogenesis and substrate oxidation are not different between lean and obese women after two different isocaloric meals, one rich in protein and one rich in fat.

Reduction in diet-induced thermogenesis (DIT) may promote weight gain and maintenance. Data on differences in DIT and macronutrient oxidation between lean and obese subjects are conflicting. In this study, we sought for differences in DIT and macronutrient oxidation between lean and obese women after consumption of 2 different isocaloric meals, one rich in protein and one rich in fat. Fifteen lean and 15 obese women were studied on 2 occasions, 1 week apart. In one visit, they consumed a protein-rich meal; in the other visit, a fat-rich meal. The 2 meals were isocaloric ( approximately 2026 kJ each), of equal volume, and given in random order. Resting energy expenditure and macronutrient oxidation rates were measured and calculated in the fasting state and every 1 hour for 3 hours after meal consumption. Diet-induced thermogenesis was not significantly different between lean and obese subjects after consumption of either the protein-rich (P = .59) or the fat-rich meal (P = .68). Diet-induced thermogenesis was significantly higher (by almost 3-fold) after consumption of the protein-rich meal in comparison with the fat-rich meal in both study groups. In addition, no significant differences in macronutrient oxidation rates were found between lean and obese women after the test meals. The results indicate that DIT is higher after protein intake than after fat intake in both lean and obese participants; however, DIT and macronutrient oxidation rate are not different between lean and obese subjects after consumption of either a protein-rich or a fat-rich meal. Over the long term, a low DIT after regular or frequent fat intake may contribute to the development and maintenance of obesity.

The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes

BACKGROUND Cardiac autonomic neuropathy (CAN) is a common diabetes complication associated with poor prognosis. This cross-sectional study aimed to examine for associations between CAN and metabolic and other parameters in patients with either type 1 (T1DM) or type 2 (T2DM) diabetes. PATIENTS AND METHODS A total of 600 patients (T1DM, n=200; T2DM, n=400) were recruited. Participants with overt nephropathy, macrovascular complications, and treated hypertension were excluded. CAN was diagnosed when two of the four classical autonomic function tests were abnormal. RESULTS CAN was diagnosed in 42.0% and in 44.3% of the participants with T1DM and T2DM, respectively. Multivariate logistic regression analysis demonstrated that, in T1DM, the odds [OR (95% confidence intervals)] of CAN increased with higher waist circumference [1.36 (1.01-2.02)], systolic blood pressure [1.16 (1.03-1.31)], hypertension [1.19 (1.03-2.67)], smoking [1.10 (1.12-1.40], fasting glucose [1.01 (1.00-1.01)], HbA(1c) [1.69 (1.07-2.76)], pubertal diabetes onset [1.08 (1.03-1.24)], LDL cholesterol [1.01(1.00-1.02)], triglycerides [1.58 (1.24-1.48)], retinopathy [1.13 (1.04-1.41)], peripheral neuropathy [2.53 (1.07-2.99)], glomerular filtration rate [0.93 (0.87-0.99)], and microalbuminuria [1.24 (1.12-1.36)]. The same analysis in T2DM demonstrated that the odds of CAN increased with higher waist circumference [1.08 (1.00-1.39)], systolic blood pressure [1.06 (1.02-1.12)], hypertension [1.50 (1.24-2.03)], smoking [1.22 (1.14-1.49)], diabetes duration [1.20 (1.09-1.34)], fasting glucose [1.21 (1.12-1.31)], HbA(1c) [1.25 (1.08-1.45)], LDL cholesterol [1.35 (1.04-1.75)], triglycerides [1.30 (1.00-1.68)], retinopathy [1.24 (1.16-1.35)], peripheral neuropathy [1.79 (1.07-2.01)], glomerular filtration rate [0.96 (0.95-0.97)], and microalbuminuria [1.20 (1.14-1.36)]. CONCLUSIONS CAN is common in diabetes and is associated with modifiable factors including central fat distribution, hypertension, dyslipidemia, worse diabetes control, and smoking, and with the other microvascular complications of diabetes. Our findings emphasize the need for a multifactorial intervention for the prevention of CAN.

The effect of ingested macronutrients on postprandial ghrelin response: a critical review of existing literature data.

Ghrelin is a powerful orexigenic gut hormone with growth hormone releasing activity. It plays a pivotal role for long-term energy balance and short-term food intake. It is also recognized as a potent signal for meal initiation. Ghrelin levels rise sharply before feeding onset, and are strongly suppressed by food ingestion. Postprandial ghrelin response is totally macronutrient specific in normal weight subjects, but is rather independent of macronutrient composition in obese. In rodents and lean individuals, isoenergetic meals of different macronutrient content suppress ghrelin to a variable extent. Carbohydrate appears to be the most effective macronutrient for ghrelin suppression, because of its rapid absorption and insulin-secreting effect. Protein induces prolonged ghrelin suppression and is considered to be the most satiating macronutrient. Fat, on the other hand, exhibits rather weak and insufficient ghrelin-suppressing capacity. The principal mediators involved in meal-induced ghrelin regulation are glucose, insulin, gastrointestinal hormones released in the postabsorptive phase, vagal activity, gastric emptying rate, and postprandial alterations in intestinal osmolarity.

Moisture Status of the Skin of the Feet Assessed by the Visual Test Neuropad Correlates With Foot Ulceration in Diabetes

OBJECTIVE To examine the association between the moisture status of the skin of the feet with foot ulceration in subjects with diabetes. RESEARCH DESIGN AND METHODS A total of 379 subjects with diabetes were examined. Assessment of peripheral neuropathy was based on neuropathy symptom score, neuropathy disability score, vibration perception threshold, and the 10-g monofilament perception. The moisture status of the skin of the feet was assessed using the visual test Neuropad. RESULTS Patients with foot ulceration had more severe peripheral neuropathy and more often an abnormal Neuropad response. Multivariate logistic regression analysis demonstrated that the odds of foot ulceration increased with measures of neuropathy but increased also with an abnormal Neuropad response. CONCLUSIONS An abnormal Neuropad response correlates with foot ulceration in subjects with diabetes. This finding, if confirmed prospectively, suggests that the Neuropad test may be included in the screening tests for the prediction of foot ulceration.

Meal-induced thermogenesis and macronutrient oxidation in lean and obese women after consumption of carbohydrate-rich and fat-rich meals

OBJECTIVE To examine differences in meal-induced thermogenesis and macronutrient oxidation between lean and obese women after consumption of two different isocaloric meals, one rich in carbohydrate (CHO) and one rich in fat. METHODS A total of 19 lean and 22 obese women were studied on two occasions, 1 wk apart. In one visit they consumed a CHO-rich meal and in the other visit a fat-rich meal. The two meals were isocaloric and were given in random order. Resting energy expenditure and macronutrient oxidation rates were measured and calculated in the fasting state and every hour for 3 h after meal consumption. RESULTS Meal-induced thermogenesis was not different between lean and obese subjects after the CHO-rich (P = 0.89) or fat-rich (P = 0.32) meal, but it was significantly higher after the CHO-rich compared with the fat-rich meal in the lean and the obese individuals (P < 0.05). Protein oxidation rate increased slightly but significantly after the test meals in both groups (P < 0.01). Fat oxidation rate decreased after consumption of the CHO-rich meal (P < 0.001), whereas it increased after consumption of the fat-rich meal in both groups (P < 0.01). CHO oxidation rate increased in both groups after consumption of the CHO-rich meal (P < 0.001). Oxidation rates of protein, fat, and CHO during the experiment were not significantly different between lean and obese participants. CONCLUSION Meal-induced thermogenesis and macronutrient oxidation rates were not significantly different between lean and obese women after consumption of a CHO-rich or a fat-rich meal.

Plasma levels of MMP-2, MMP-9 and TIMP-1 are not associated with arterial stiffness in subjects with type 2 diabetes mellitus

OBJECTIVE Increased arterial stiffness is a marker of atherosclerosis and is recognised early in the course of type 2 diabetes mellitus (T2DM). Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are a family of proteolytic enzymes which are essential for the structure and function of large arteries. In this study, we examined for relationships between MMP and TIMP-1 and indices of arterial stiffness in subjects with T2DM. RESEARCH DESIGN AND METHODS A total of 60 subjects with T2DM and 60 nondiabetic subjects were recruited. Aortic distensibility (AD) was assessed noninvasively by ultrasonography and augmentation index by pulse wave analysis. RESULTS The values of AD were lower in subjects with T2DM than in controls (P<.001), while those of augmentation index were not significantly different between the two groups. Plasma concentrations of MMP-2 and MMP-9 were not different between diabetic and nondiabetic participants, while those of TIMP-1 were lower in the diabetic patients (P=.005). In the diabetes group, no significant associations were found between either AD or augmentation index and MMPs as well as TIMP-1, while duration of diabetes emerged as the strongest predictor of AD (P<.001). In the nondiabetic group, nonsignificant associations were also found between AD or augmentation index and MMPs as well as TIMP-1. CONCLUSION In patients with T2DM, plasma levels of MMP and TIMP-1 are not associated with arterial stiffness assessed by either AD or augmentation index.

Differences in plasma apelin and visfatin levels between patients with type 1 diabetes mellitus and healthy subjects and response after acute hyperglycemia and insulin administration.

OBJECTIVE. Previous data suggest that apelin and visfatin play a role in metabolism and glucose homeostasis. The aim of the present study was to determine differences in plasma apelin and visfatin concentrations between healthy subjects and patients with type 1 diabetes mellitus and to study the effect of hyperglycemia and insulin administration on their levels in patients with type 1 diabetes mellitus. DESIGN. One hundred patients with T1DM and 52 healthy subjects were examined. Nine patients with type 1 diabetes and 9 controls participated in a further study. In the main study, blood samples were taken after a 12-hour fast. In a further study, an oral glucose tolerance test was performed on two occasions. In session A, at baseline, insulin lispro (7 units) was administered subcutaneously to the type 1 diabetic patients, while a placebo injection was administered to controls. In session B, no insulin or placebo was administered. Apelin, visfatin, insulin and glucose levels were measured at baseline and 10, 20, 30, 60, 90, 120, 150 and 180 min after glucose consumption. RESULTS AND CONCLUSIONS. Fasting plasma apelin concentrations were higher (p<0.001), while fasting visfatin levels tended to be lower (p=0.06) in patients with type 1 diabetes in comparison to healthy subjects. In the diabetes group, fasting apelin (but not visfatin) correlated with HDL-C (p = 0.001). Apelin and visfatin did not change significantly during the oral glucose tolerance test in either group with or without exogenous insulin administration.