Improved glycaemia in type 1 diabetes results in decreased levels of soluble adhesion molecules with no change in serum adiponectin or most acute phase proteins.

AIMS: To investigate how reduction of hyperglycaemia affects acute phase serum proteins in poorly controlled type 1 diabetic patients. METHODS: 24 patients (age 31.7 +/- 2.0 years, HbA1c 9.3 +/- 0.2%, BMI 24.2 +/- 0.7 kg/m2, diabetes duration 15.3 +/- 1.7 years) participated in the study. The treatment was optimised for 16 weeks. Blood samples were taken at baseline and at the end of the study. 16 healthy age- and BMI-matched subjects were chosen for a control group. RESULTS: At baseline, the patients had higher C-reactive protein (CRP) (1.09, median [range 0.24-18.82] mg/l vs. 0.66 [0.18-2.46] mg/l, p < 0.02), mean adiponectin (16.06 +/- 1.31 vs. 8.85 +/- 0.93 mg/l, p < 0.001), ceruloplasmin (306 +/- 16.1 vs. 205.4 +/- 5.5 mg/l, p < 0.001), fibrinogen (3.41 +/- 0.26 vs. 2.38 +/- 0.07 g/l, p < 0.001), soluble intercellular adhesion molecule-1 (sICAM-1) (255.4 +/- 10.3 vs. 194 +/- 10.6 microg/l, p < 0.001), soluble vascular adhesion molecule-1 (sVCAM-1) (533.4 +/- 21.8 vs. 422.9 +/- 20.7 microg/l, p < 0.01) and interleukin-6 (2.89 +/- 0.49 vs. 1.35 +/- 0.30 ng/l, p < 0.01) concentrations than the controls. During intensified treatment, HbA1c decreased (to 8.5 +/- 0.2%, p < 0.001). This resulted in reduced sE-selectin (from 44.6 +/- 2.6 to 38.8 +/- 2.6 microg/l, p < 0.01), alpha-1-acid-glycoprotein (A1GP) (from 622.9 +/- 47.9 to 525.7 +/- 27.9 mg/l, p < 0.01), sICAM-1 (from 255.4 +/- 10.3 to 240.8 +/- 9.1 microg/l, p < 0.05) and IL-6 (from 2.9 +/- 0.5 to 2.1 +/- 0.4 ng/l, p < 0.01). Serum amyloid A (SAA) and CRP did not change 12.00 (0.7-222.0) vs. 12.00 (1.6-277.0) mg/l for SAA and 1.09 (0.24-18.82) vs. 1.09 (0.18-23.08) mg/l for CRP, baseline vs. treatment, respectively. CONCLUSIONS: Poorly controlled type 1 diabetic patients have increased values of adiponectin, CRP, ceruloplasmin, fibrinogen, sICAM-1, sVCAM-1 and IL-6. Reduction of hyperglycaemia results in decreased sE-selectin, A1GP, sICAM-1 and IL6, while other inflammatory factors including CRP, SAA and adiponectin are not affected.

Plasma IL-6 concentration is inversely related to insulin sensitivity, and acute-phase proteins associate with glucose and lipid metabolism in healthy subjects.

AIM: It has been shown that atherosclerosis is an inflammatory disease. Recent data suggest that inflammation precedes type 2 diabetes. Hence, we wanted to study the interrelationship between IL-6, insulin sensitivity, lipids and numerous acute-phase proteins. METHODS: Twenty-one healthy individuals [16 males/5 females, age 27.9+/-1.8 years, body mass index (BMI) 24.1+/-0.8 kg/m(2)] participated in the study. Each patient went through a 4-h hyperinsulinaemic (40 mU/m(2)/min) euglycaemic clamp and 4-h saline infusion. Blood samples were taken before and at the end of the infusions. RESULTS: Plasma interleukin (IL)-6 concentration correlated inversely with insulin sensitivity (M-value) (r=-0.49, p<0.05). Moreover, the plasma levels of IL-6 associated with c-peptide (r=0.49, p<0.05), fat% (r=0.43, p<0.05) and diastolic blood pressure (r=0.46, p<0.05). alpha-1-acid glycoprotein was related to HbA1(c) (r=0.47, p<0.05), insulin (r=0.55, p<0.01), diastolic blood pressure (r=0.58, p<0.01), systolic blood pressure (r=0.58, p<0.01) and triglycerides (r=0.58, p<0.01). Haptoglobin was correlated with insulin (r=0.46, p<0.05), total cholesterol (r=0.61, p<0.01), BMI (r=0.58, p<0.01), fat% (r=0.63, p<0.01) and lipid oxidation during clamp (r=0.43, p<0.05). Diastolic blood pressure decreased during the clamp (from 78.3+/-1.9 to 72.1+/-2.0 mmHg, p=0.001). Insulin infusion did not affect the serum levels of most acute-phase proteins. CONCLUSIONS: Our study suggests that low grade inflammation, as reflected by IL-6, A1GP and haptoglobin contributes to the regulation of insulin sensitivity, lipid metabolism and blood pressure in normal human physiology.

Carbohydrate depletion has profound effects on the muscle amino acid and glucose metabolism during hyperinsulinaemia.

AIM: We investigated the effect of carbohydrate availability and euglycaemic hyperinsulinaemia on intramuscular and plasma amino acids in 14 healthy men (age 26.5 +/- 0.9 years, b.m.i. 22.9 +/- 0.5 kg/m2). METHODS: Insulin was infused (1.5 mU/kg/min) for 240 min both after a carbohydrate depleting exercise and after carbohydrate loading. Muscle samples were taken before and after hyperinsulinaemia. Plasma and intramuscular amino acid concentrations were measured. RESULTS: Insulin-mediated glucose disposal was similar after carbohydrate depletion (65.2 +/- 1.9 micromol/kg/min) and loading (66.9 +/- 2.8 micromol/kg/min). Carbohydrate depletion was associated with decreased alanine and increased branched chain amino acid (BCAA) concentrations in muscle and plasma. Blood lactate was lower after carbohydrate depletion (477 +/- 25 micromol/l) than loading (850 +/- 76 micromol/l, p < 0.001). In carbohydrate depletion, hyperinsulinaemia resulted in a greater increase in intramuscular (from 927 +/- 48 nmol/g muscle to 2029 +/- 104 nmol/g muscle, p < 0.001), than plasma (from 197 +/- 6.7 micromol/l to 267 +/- 11 micromol/l, p < 0.001) alanine. After carbohydrate loading muscle alanine did not rise significantly (from 1546 +/- 112 nmol/g muscle to 1781 +/- 71 nmol/g muscle) whereas plasma alanine decreased (from 339 +/- 26 micromol/l to 272 +/- 13 micromol/l, p < 0.05). CONCLUSIONS: (1) Carbohydrate availability has profound effects on the interrelationship between glucose and amino acid metabolism and on the form of storage for glucose-derived carbons. (2) For most amino acids changes in plasma levels of amino acids are not related to changes in concentrations of intramuscular amino acids during hyperinsulinaemia.

Oesophageal acid exposure: higher in Barrett's oesophagus than in reflux oesophagitis.

Oesophageal acid exposure at different pH intervals between 0 and 8 in patients with Barrett's oesophagus (n = 24) was compared with that in patients with reflux oesophagitis (n = 19) by using 24-h pH monitoring. Prior to the monitoring, the position and pressure of the lower oesophageal sphincter was measured by manometry. Columnar epithelium with intestinal metaplasia and goblet cells was verified histologically in all Barrett patients and grade I-III oesophagitis in patients with reflux oesophagitis. Acid exposure (percentage of total time at pH < 4) in the Barrett group was significantly greater than in the oesophagitis group: 21.5+/-20.0% SD vs 11.1+/-11.7% SD (P < 0.01). The number of reflux episodes lasting longer than 5 min (representing oesophageal body clearance function) was also significantly greater in the Barrett group (8.3+/-5.9 SD) than in the oesophagitis group (4.5+/-4.7 SD) (P < 0.01). In the Barrett group the acid exposure time was greater at all pH intervals 0-1, 1-2, 2-3 and 3-4, (P < 0.01) but in the oesophagitis group the exposure time was greater at pH interval 5-6 (P < 0.01). There was no significant difference in exposure at pH values above 7. The mean lower oesophageal sphincter pressure was equal in both groups (11.0 vs 11.9 mmHg). In conclusion, oesophageal acid exposure was significantly greater in Barrett's oesophagus than in reflux oesophagitis, and this was associated with decreased oesophageal clearance function. In addition, the results indicated the need for special attention and perhaps higher dosages of drugs to suppress acid production in patients with Barrett's oesophagus.

Lispro Mix25 insulin as premeal therapy in type 2 diabetic patients.

OBJECTIVE: Insulin Mix25 is a new premixed insulin analog containing 25% insulin lispro and 75% neutral protamine lispro (NPL) suspension (NPL insulin). The aim of the study was to compare serum glucose and insulin responses after breakfast in type 2 diabetic patients who received Mix25, premixed regular/NPH (30%/70%), or NPH insulin before the meal. RESEARCH DESIGN AND METHODS: We studied 22 type 2 diabetic patients of age 62 +/- 1 years, BMI 30 +/- 1 kg/m2, duration of diabetes 15 +/- 2 years, duration of insulin therapy 6 +/- 1 years, insulin dose 65 +/- 6 U/day, and HbA1c 7.9 +/- 0.2%. Ten healthy individuals (age 56 +/- 1 years, BMI 28 +/- 1 kg/m2) served as control subjects. Each patient (except healthy subjects, who were studied once each) was studied three times in a double-blind, randomized fashion. After an overnight fast, the patients received 36 +/- 4 U of test insulin. Ten minutes after insulin injection, the patients ingested a breakfast meal (512 kcal, 60% carbohydrate, 20% fat, and 20% protein), identical in all studies. Blood samples were taken before and at 10- to 30-min intervals for 240 min after the breakfast meal. RESULTS: The peak rise in serum glucose was lower after Mix25 (76 +/- 7 mg/dl) than after 30/70 (94 +/- 5 mg/dl, P < 0.05) or NPH (113 +/- 4 mg/dl, P < 0.005) insulin. The incremental area under the serum glucose curve was 36% smaller after Mix25 than after 30/70 (P < 0.01) and 56% smaller than after NPH (P < 0.005) insulin. The peak rise in serum insulin concentration was higher after Mix25 (103 +/- 18 mU/l) than after 30/70 (87 +/- 13 mU/l, P < 0.05) or NPH (62 +/- 12 mU/l, P < 0.01) insulin. The incremental area under the serum insulin curve was higher after Mix25 than after 30/70 during the first 2-3 h (P < 0.02), but the difference disappeared by the end of the 4-h follow-up period. After Mix25 injection, there was an inverse correlation between the glucose response to a meal and insulin dose (r = -0.56, P < 0.01) or the incremental area under the serum insulin curve (r = -0.39, P < 0.05). No such correlations were observed with the other insulins. CONCLUSIONS: Because of its faster initial absorption rate, the new premixed insulin analog Mix25 reduces blood glucose response to a breakfast meal in type 2 diabetic patients compared with premixed 30/70 (regular/NPH) or NPH insulin.

Long-term lisinopril therapy reduces exercise-induced albuminuria in normoalbuminuric normotensive IDDM patients.

OBJECTIVE: To study the effect of lisinopril on the exercise-induced urinary albumin excretion rate. RESEARCH DESIGN AND METHODS: A total of 26 IDDM patients with normoalbuminuria were randomized into two groups, with one group receiving placebo (n = 13, age 36 +/- 3 years, BMI 24.5 +/- 1.1 kg/m2) and the other group receiving an average of 15 mg lisinopril daily (n = 13, age 34 +/- 2 years, BMI 24.4 +/- 0.9 kg/m2). Overnight and exercise-induced urinary albumin excretion rate was measured at baseline and after 1 and 2 years of treatment. Two patients in the placebo group and none in the lisinopril group developed microalbuminuria. RESULTS: In the lisinopril group, the exercise-induced urinary albumin excretion rate diminished 46% after the 1st year (P = 0.059) and 66% (P < 0.01) after the 2nd year. However, it remained unchanged in the control group. Systolic blood pressure (sBP) and diastolic blood pressure (dBP) were similar at baseline and after 1 year, but at 2 years, sBP was 13 mmHg lower (P = 0.03) and dBP was 9 mmHg lower (P = 0.052) in the lisinopril group as compared with the control group. The dBP decreased significantly at 1 and 2 years in the lisinopril group, while there was no significant change in the sBP. In the whole group at baseline, the overnight albumin excretion rate correlated with HbA1c (r = 0.50, P < 0.01) and the duration of diabetes (r = 0.39, P < 0.05), and sBP correlated with both the overnight (r = 0.42, P < 0.05) and the exercise-induced (r = 0.48, P < 0.05) albumin excretion rate. CONCLUSIONS: Glycemic control and blood pressure are directly related to the overnight albumin excretion rate also in normotensive normoalbuminuric IDDM patients. Lisinopril treatment reduces the exercise-induced urinary albumin excretion rate in such patients. These data suggest a protective effect of lisinopril against the development of microalbuminuria.

The effect of exercise on leptin concentration in healthy men and in type 1 diabetic patients.

PURPOSE: Leptin is a recently discovered hormone that appears as a regulator of energy balance. It is important to know whether leptin concentrations are changed under conditions of altered energy homeostasis. Consequently, we examined the effects of exercise with fasting and exercise with feeding on circulating leptin concentrations in healthy men and in type 1 diabetic patients with normal body weight and well controlled diabetes. METHODS: Leptin concentrations were determined with radioimmunoassay. RESULTS: During a 3-h cycle ergometer exercise with fasting, leptin decreased by 42% (P < 0.01) in nine healthy men and by 23% (P = 0.05) in eight male type 1 diabetic patients. Leptin fell equally by 12% (P < 0.03) both in nine healthy men and in eight male type 1 diabetic patients who were studied as a resting control group. The absolute fall in leptin in healthy men was similar in the exercise and resting control groups (0.8 +/- 0.1 microgram.L-1 vs 0.8 +/- 0.2 microgram.L-1). However, due to lower leptin concentration before the exercise, the relative decrease (42%) was greater than during the resting control study (12%, P < 0.005). This difference was not seen in the diabetic patients. Fasting leptin concentration correlated positively with BMI (r = 0.75, P < 0.001) and fasting insulin (r = 0.71, P < 0.01) in healthy men as well as with insulin level (r = 0.54, p < 0.05) in type 1 diabetic patients. When exercise was performed with feeding, and this was associated with a significant rise in serum cortisol level (marathon run, 14 healthy men and 7 type 1 diabetic patients), leptin concentration did not change significantly. CONCLUSIONS: 1) During morning hours, leptin decreases both in healthy men and in type 1 diabetic patients, reflecting a diurnal variation of leptin concentration and the effect of fasting on leptin concentration. 2) The fall in leptin during morning hours is augmented by physical exercise in healthy men. 3) If exercise is performed with feeding and associated with a rise in serum cortisol level, leptin concentration remains unchanged. These data suggest that although exercise may reduce circulating leptin levels, the effect is small and can be counterbalanced by feeding or a rise in serum cortisol concentration.

Intramuscular triglyceride content is increased in IDDM.

UNLABELLED: Increased lipid oxidation is related to insulin resistance. Some of the enhanced lipid utilization may be derived from intramuscular sources. We studied muscle triglyceride (mTG) concentration and its relationship to insulin sensitivity in 10 healthy men (age 29 +/- 2 years, BMI 23.3 +/- 0.6 kg/m2) and 17 men with insulin-dependent diabetes mellitus (IDDM) (age 30 +/- 2 years, BMI 22.8 +/- 0.5 kg/m2, diabetes duration 14 +/- 2 years, HbA1c 7.7 +/- 0.3%, insulin dose 48 +/- 3 U/day). Insulin sensitivity was measured with a 4h euglycaemic (5 mmol/l) hyperinsulinaemic (1.5 mU or 9 pmol x kg(-1) x min[-1]) clamp accompanied by indirect calorimetry before and at the end of the insulin infusion. A percutaneous biopsy was performed from m. vastus lateralis for the determination of mTG. At baseline the IDDM patients had higher glucose (10.2 +/- 0.9 vs 5.6 +/- 0.1 mmol/l, p < 0.001), insulin (40.3 +/- 3.2 vs 23.2 +/- 4.2 pmol/l, p < 0.01), HDL cholesterol (1.28 +/- 0.06 vs 1.04 +/- 0.03 mmol/l, p < 0.01) and mTG (32.9 +/- 4.6 vs 13.6 +/- 2.7 mmol/kg dry weight, p < 0.01) concentrations than the healthy men, respectively. The IDDM patients had lower insulin stimulated whole body total (-25%, p < 0.001), oxidative (-18%, p < 0.01) and non-oxidative glucose disposal rates (-43%, p < 0.001), whereas lipid oxidation rate was higher in the basal state (+ 44%, p < 0.01) and during hyperinsulinaemia (+283%, p < 0.05). mTG concentrations did not change significantly during the clamp or correlate with insulin stimulated glucose disposal. In healthy men mTG correlated positively with lipid oxidation rate at the end of hyperinsulinaemia (r = 0.75, p < 0.05). IN CONCLUSION: 1) IDDM is associated with increased intramuscular TG content. 2) mTG content does not correlate with insulin sensitivity in healthy subjects or patients with IDDM.

Blood flow, lipid oxidation, and muscle glycogen synthesis after glycogen depletion by strenuous exercise.

UNLABELLED: We studied the interrelationship between blood flow, glycogen synthesis, and glucose and lipid utilization in 14 healthy men. A 4-h euglycemic insulin clamp with indirect calorimetry and muscle biopsies were done after a glycogen depletion (exercise) and after a resting day (control). In spite of the exercise induced decrease in leg muscle glycogen content (28% in the basal state, 22% after hyperinsulinemia, P < 0.05 in both as compared with the control study), basal or insulin stimulated glycogen synthase activity remained unchanged. In the basal state, glucose oxidation was 54% lower (P < 0.001) and lipid oxidation 108% higher (P < 0.001) after the glycogen depletion as compared with that in the control study. During the post-depletion insulin clamp, the glucose oxidation rate was 17% lower (P < 0.02) and lipid oxidation 169% higher (P < 0.01), while the whole body total glucose disposal was similar in both studies. Baseline forearm blood flow was similar and increased equally by over 40% during both insulin clamp studies (P < 0.05). Basal glucose extraction after glycogen depletion study was one third of that in the control study (P < 0.05). Both basal and insulin stimulated leg muscle glycogen content correlated inversely with basal forearm blood flow (r = -0.69, P < 0.01 and r = -0.82, P < 0.001, respectively) and basal lipid oxidation (r = -0.54, P < 0.05 and r = -0.64, P < 0.01, respectively) after glycogen depletion. Basal glycogen synthase fractional activity correlated positively with forearm blood flow (r = 0.78, P < 0.001) and forearm glucose uptake (r = 0.71, P < 0.05) during the insulin infusion. IN CONCLUSION: 1) the unchanged insulin sensitivity in the face of glycogen depletion is probably a result of increased lipid oxidation, and 2) blood flow is related inversely to muscle glycogen content and directly to glycogen synthase activity.

Leptin and thermogenesis in humans.

We examined changes in serum leptin concentrations and thermogenesis in 12 healthy men (39 +/- 2 years, BMI 22.8 +/- 0.3 kg m-2) during a 4 h euglycaemic hyperinsulinaemia performed on a control day and after a day of competitive marathon runs. As compared with the control day, after the marathon, baseline FFA concentration (543 +/- 0.73 vs. 955 +/- 96 mumol L-1, P < 0.05), lipid oxidation rate (0.8 +/- 0.1 vs. 1.2 +/- 0.1 mg kg-1 min-1, P < 0.01) and energy expenditure (5.2 +/- 0.1 vs. 5.5 +/- 0.1 kJ min-1, P < 0.01) were elevated. Baseline serum leptin concentrations were similar on the control and postexercise days and increased during insulin infusion by 35-45% on both days (P < or = 0.01). Baseline serum leptin concentration correlated directly with serum insulin (r = 0.65, P < 0.05) and cortisol (r = 0.64, P < 0.05), and inversely with serum growth hormone concentration (r = -0.66, P < 0.05). In the postexercise study, the rise in energy expenditure during insulin clamp correlated with serum leptin concentration as determined before (r = 0.61, P < 0.05) or at the end of insulin infusion (r = 0.55, P < 0.05). Thus, in healthy individuals with normal body weight: (1) hyperinsulinaemia increases serum leptin concentrations; (2) a rise in energy expenditure correlates with serum leptin concentration. These data suggest that leptin is involved in the regulation of energy expenditure in humans.

Metabolic response to lactitol and xylitol in healthy men.

Sugar alcohols are used in food products, yet their metabolic effects in humans are poorly known. We examined plasma glucose, insulin, and C-peptide responses and changes in carbohydrate and lipid oxidation after the ingestion of 25 g lactitol, xylitol, or glucose. Eight healthy, nonobese men were studied after an overnight fast. After the ingestion of lactitol or xylitol, the rise in plasma glucose, insulin, and C-peptide concentrations was less than after the ingestion of glucose (P < 0.02), with no difference between the two polyols. With the glycemic index of glucose as 100, the indexes of xylitol and lactitol were 7 and -1, respectively. A reactive hypoglycemia was observed 3 h after glucose ingestion, but not after the ingestion of sugar alcohols. There were no significant changes in the carbohydrate or lipid oxidation as determined by indirect calorimetry after the ingestion of sugar alcohols. After glucose ingestion, the rise in carbohydrate oxidation was nearly significant (P = 0.07). In conclusion, lactitol and xylitol cause smaller changes than does glucose in plasma glucose and insulin concentrations and thermogenic response. A small hormonal response and the lack of a thermogenic effect may be beneficial when these sugar alcohols are used in food products. The small glucose and insulin responses also suggest that lactitol and xylitol are suitable components of the diet for diabetic patients.

Post-marathon paradox in IDDM: unchanged insulin sensitivity in spite of glycogen depletion.

UNLABELLED: Acute physical exercise usually enhances insulin sensitivity. We examined the effect of a competitive 42 km marathon run on glucose uptake and lipid oxidation in 7 runners with insulin-dependent diabetes mellitus (IDDM), aged 36 +/- 3 yr, BMI 23.9 +/- 0.5 kg m-2, VO2max 46 +/- 1 ml kg-1 min-1, HbA1c 7.7 +/- 0.3%, duration of diabetes 16 +/- 5 yr, runtime 3 h 47 +/- 8 min. On the marathon day, they reduced pre-race insulin doses by 26 +/- 8%, and ingested 130 +/- 33 g carbohydrate before, 91 +/- 26 g during, and 115 +/- 20 g after the race. During the run, blood glucose concentration fell from 14.4 +/- 2.0 to 7.4 +/- 3.0 mmol l-1 (p < 0.05) and serum insulin from 51 +/- 8 to 33 +/- 8 pmol l-1 (p < 0.05). Serum NEFA increased by 4-fold (p < 0.05), but fell to the normal level by next morning. Muscle glycogen content was 56% lower (p < 0.05) and glycogen synthase fractional activity 40% greater (p < 0.05) in the morning after the marathon as compared to the resting control day. In spite of glycogen depletion, whole body glucose disposal (euglycaemic insulin clamp) was unchanged, while glucose oxidation (indirect calorimetry) was decreased by 49% (p < 0.05) and lipid oxidation increased by 41% (p < 0.01). There was an inverse correlation between the rates of lipid oxidation and glucose uptake after the marathon (r = -0.75; p < 0.05). IN CONCLUSION: after successfully managed marathon running in patients with IDDM, insulin sensitivity was not increased in spite of low glycogen content and enhanced glycogen synthase activity after marathon, probably because of increased lipid oxidation.

Serum leptin concentration and fuel homeostasis in healthy man.

We studied the interrelationship between the obese gene product serum leptin, insulin and counter-regulatory hormone concentrations and glycogen synthesis in 26 healthy men. A 4-h euglycaemic insulin clamp with muscle biopsies was performed after a resting control day in 26 subjects, and in 14 of them also after heavy, glycogen-depleting (32%, P < 0.01) exercise. Serum leptin concentrations were at baseline 34% (0.67 +/- 0.18 vs. 1.03 +/- 0.13 ng L-1, P < 0.05) lower after the exercise, and rose during hyperinsulinaemia by 56% (to 1.38 +/- 0.19 ng L-1, P < 0.001) and 34% (to 1.05 +/- 0.20 ng L-1, P < 0.01) after the post-exercise and control studies respectively. Basal serum leptin concentration correlated positively with body mass index (r = 0.42, P < 0.05), serum cortisol concentration (r = 0.70, P < 0.001) and the rise in muscle glycogen content during the clamp (r = 0.43, P < 0.05) and inversely with serum growth hormone concentration (r = -0.43, P < 0.05). There was a positive correlation between serum leptin after hyperinsulinaemia and serum insulin concentration during the hyperinsulinaemia (r = 0.42, P < 0.05). After exercise, basal serum leptin level correlated with serum triglyceride concentration (r = 0.82, P < 0.001) and after hyperinsulinaemi serum leptin correlated positively with muscle glycogen content (r = 0.56, P < 0.05). It was concluded that serum leptin concentrations correlate directly with serum insulin, cortisol and triglyceride and inversely with growth hormone concentrations. They are decreased by glycogen-depleting exercise and increase during hyperinsulinaemic clamp. These data suggest that leptin is associated with factors regulating fuel homeostasis and its hormonal control in man.

Leptin synthesis is resistant to acute effects of insulin in insulin-dependent diabetes mellitus patients.

Insulin stimulates ob gene expression and increases serum leptin concentrations in mice and in noninsulin-dependent diabetes mellitus patients. Obese women have higher ob gene messenger ribonucleic acid levels than obese men, suggesting that sex hormones are involved in the regulation of leptin synthesis. We studied the relationship among leptin, insulin, and testosterone in 15 men with insulin-dependent diabetes mellitus (IDDM; age, 29 +/- 2 yr; body mass index, 22.7 +/- 0.5 kg/m2; body fat, 9.5 +/- 1.0%; insulin dose, 44 +/- 4 U/day; hemoglobin A1c, 8.1 +/- 0.3%; diabetes duration, 12.7 +/- 2.0 yr) and 15 healthy control subjects (age, 27 +/- 1 yr; body mass index, 22.6 +/- 0.4 kg/m2; body fat, 9.6 +/- 0.5%) in the fasting state. In addition, the effect of a 4-h euglycemic hyperinsulinemia (approximately 600 pmol/L) on the plasma leptin concentration was determined. The fasting leptin concentration was negatively correlated to plasma testosterone (r = -0.55; P < 0.05) in IDDM patients. The fasting plasma leptin level rose 25% in healthy subjects (from 1.0 +/- 0.2 to 1.3 +/- 0.3 ng/mL; P < 0.05). The leptin levels were higher in IDDM subjects (P < 0.01) and remained unchanged (2.7 +/- 0.2 vs. 2.7 +/- 0.2 ng/mL) during hyperinsulinemia. We reached the following conclusions. 1) In nonobese IDDM patients, leptin synthesis is resistant to the acute effect of insulin. 2) Serum testosterone may contribute to the regulation of leptin synthesis in IDDM patients.

Exercise increases insulin clearance in healthy man and insulin-dependent diabetes mellitus patients.

Exercise is known to decrease insulin secretion, but the effect on insulin clearance is unclear. We examined the effect of exercise in insulin clearance with euglycaemic insulin clamp in 28 healthy men either 12 h after a marathon run (n = 14) or 44 h after a 2-h treadmill exercise (n = 14), and in seven insulin-dependent diabetes mellitus (IDDM) patients 12 h after a marathon run, and after a resting, control day. During the post-exercise insulin infusion, steady-state plasma insulin concentration was reduced by 9% in healthy men after both types of exercise, and by 16% in the diabetic subjects compared with the control study (P < 0.05 in all). In healthy men, C-peptide concentrations were more than one-third lower during insulin infusion, both after the marathon run (P < 0.001) or treadmill exercise (P < 0.02) compared with the control study. Insulin clearance was significantly increased by exercise both in healthy men (9% P < 0.05) and in IDDM subjects (15%, P < 0.05). After exercise, endogenous insulin secretion in healthy men is reduced and insulin clearance is enhanced both in healthy men and in IDDM patients. Decreased insulin availability may allow enhanced muscle lipid utilization and spare glucose after long-term exercise.

pH-metric analysis after successful antireflux surgery: comparison of 24-hour pH profiles in patients undergoing floppy fundoplication or Roux-en-Y duodenal diversion.

Fundoplication is the most widely used antireflux method, whereas Roux-en-Y duodenal diversion (partial gastrectomy, vagotomy, and Roux-en-Y reconstruction) has been used in fewer patients with more complicated gastroesophageal reflux disease. Abnormal esophageal pH values are normalized after successful fundoplication. However, very little is known about possible changes in the pH profile after successful Roux-en-Y duodenal diversion. A total of 37 patients with severe gastroesophageal reflux disease were treated by fundoplication (n=22) or Roux-en-Y duodenal diversion (n=15). Postoperatively all patients in both groups were symptom free and healing of esophagitis was verified endoscopically. After fundoplication, the 24-hour esophageal acid exposure decreased significantly (P=0.03) and the pH profile normalized (pH<4 in 5.8%+/-2.4% of the recorded time). However, the decrease in esophageal acid exposure was not significant (P=0.77) after successful Roux-en-Y reconstruction and the pH profile remained abnormal (pH<4 in 15.1%+/-4.3%). It was concluded that 24-hour esophageal pH monitoring is a reliable means of assessing the results of fundoplication, but the current test criteria should be reexamined in evaluating the results of Roux-en-Y duodenal diversion. Healing of esophagitis after Roux-en-Y duodenal diversion despite abnormal acid reflux, as shown by 24-hour pH measurements, suggests that duodenal contents also have a role in the pathogenesis of esophagitis in an acid milieu.

The association of acetyl-L-carnitine with glucose and lipid metabolism in human muscle in vivo: the effect of hyperinsulinemia.

We examined whether hyperinsulinemia is associated with changes in the amount of L-carnitine and acetyl-L-carnitine in the muscle and whether the source of acetyl-coenzyme A (CoA) (glucose or free fatty acids [FFAs]) influences its further metabolism to acetyl-L-carnitine or through tricarboxylic acid in the skeletal muscle of man in vivo. Twelve healthy men (aged 45 +/- 2 years; body mass index, 25.2 +/- 1.0 kg/m2) were studied using a 4-hour euglycemic-hyperinsulinemic clamp (1.5 mU/kg/min) and indirect calorimetry. Although the mean muscle free L-carnitine and acetyl-L-carnitine concentrations remained unchanged during hyperinsulinemia in the group as a whole, the individual changes in muscle free L-carnitine and acetyl-L-carnitine concentrations were inversely related (r = -.72, P < .02). The basal level of acetyl-L-carnitine was inversely related to the rate of lipid oxidation (r = -.70, P < .02). In a stepwise linear regression analysis, 77% of the variation in the change of acetyl-L-carnitine concentrations was explained by the basal muscle glycogen level (inversely) and nonoxidative glucose disposal rate (directly) during hyperinsulinemia (P < .001); by adding the final FFA concentration (inverse correlation) to the model, 88% of the variation was explained (P < .001). In conclusion, (1) hyperinsulinemia does not enhance skeletal muscle free L-carnitine or acetyl-L-carnitine concentrations in-man, and (2) the acetyl group of acetyl-L-carnitine in human skeletal muscle in vivo is probably mostly derived from glucose and not through beta-oxidation from fatty acids.

Acute administration of metoprolol and enalaprilat reduces insulin-stimulated thermogenesis and skin blood flow.

OBJECTIVE: To examine the acute effects of intravenous metoprolol and enalaprilat on energy expenditure, thermogenesis, blood flow and insulin sensitivity. DESIGN: Randomized, single-blind, placebo-controlled trial. SETTING: Helsinki University Central Hospital, Finland SUBJECTS: Seven moderately insulin-resistant nondiabetic subjects. INTERVENTIONS: Each subjects was studied three times at 2-3 week intervals: metoprolol (5 mg), enalaprilat (2 mg) or saline infusions were used. METHODS: A 150-min euglycaemic/hyperinsulinaemic clamp combined with indirect calorimetry and blood flow measurements were performed. MAIN OUTCOME MEASURES: Glucose uptake, forearm and skin blood flow, and energy expenditure. RESULTS: Blood pressure was decreased to the same degree by both drugs. Forearm blood flow (plethysmography) was lower with metoprolol compared to enalaprilat (2.1 +/- 0.2 vs. 2.8 +/- 0.4 mL per 100 mL min-1; P < 0.05). Glucose-plus-insulin-stimulated thermogenesis and total energy expenditures were reduced both by metoprolol (71 and 5.2%; P < 0.05 in both) and enalaprilat (59%, P = 0.06; and 7.6%, P < 0.05) as compared to the control study. Skin blood flow (laser Doppler) increased by 100% (P < 0.01) during the glucose-plus-insulin infusion, but this increment was inhibited by both drug infusions. Forearms and whole-body glucose uptake was not influenced by metoprolol or enalaprilat administration. CONCLUSIONS: (i) Both metoprolol and enalaprilat inhibit glucose-plus-insulin-induced thermogenesis and a rise in skin blood flow. (ii) Metoprolol further reduces forearm blood flow compared to enalaprilat. (iii) Neither drug has any acute effect on insulin sensitivity. (iv) The interference of a physiological response to insulin by ACE inhibitors or beta-blocking agents may have implications both for energy balance and thermoregulation during periods of hyperinsulinaemia in man.

Postmarathon paradox: insulin resistance in the face of glycogen depletion.

Acute physical exercise enhances insulin sensitivity in healthy subjects. We examined the effect of a 42-km marathon run on insulin sensitivity and lipid oxidation in 19 male runners. In the morning after the marathon run, basal serum free fatty acid concentration was 2.2-fold higher, muscle glycogen content 37% lower (P < 0.01), glycogen synthase fractional activity 56% greater (P < 0.01), and glucose oxidation reduced by 43% (P < 0.01), whereas lipid oxidation was increased by 55% (P < 0.02) compared with the control study. During euglycemic-hyperinsulinemic clamp, whole body glucose disposal was decreased by 12% (P < 0.01) because of a 36% lower glucose oxidation rate (P < 0.05), whereas the rate of lipid oxidation was 10-fold greater (P < 0.02) than in the control study. After the marathon, muscle glycogen content correlated positively with lipid oxidation (r = 0.60, P < 0.05) and maximal aerobic power (Vo2peak; r = 0.61, P < 0.05). Vo2peak correlated positively with basal lipid oxidation (r = 0.57, P < 0.05). In conclusion, 1) after the marathon run, probably because of increased lipid oxidation, the insulin-stimulated glucose disposal is decreased despite muscle glycogen depletion and the activation of glycogen synthase; 2) the contribution of lipid oxidation in energy expenditure is increased in proportion to physical fitness; 3) these adaptations of fuel homeostasis may contribute to the maintenance of physical performance after prolonged exercise.