Physical Work Capacity in Diabetic Children and Adolescents with and without Cardiovascular Autonomic Dysfunction

The aim of the present study was to evaluate the influence of autonomic nervous system dysfunction on work capacity in children and adolescents with Type 1 (insulin-dependent) diabetes. Fifteen patients with autonomic dysfunction (abnormal autonomic tests, age: 14.9±2.3 years), 35 patients without autonomic dysfunction (normal autonomic tests, age: 15.2±2.5 years), and 25 non-diabetic subjects (age: 15.0±2.3 years) were investigated. Resting heart rate, deep breathing heart rate variation, standing/lying heart rate ratio, decrease in blood pressure during orthostasis, and increase in blood pressure during sustained handgrip were used to assess cardiovascular autonomic dysfunction. Physical work capacity at heart rate of 170 min⁻¹ was determined by bicycle ergometry. Glycated haemoglobin level was higher in patients with than without autonomic dysfunction (12.3±3.1 vs 9.4±2.9%, p = 0.04). Patients with autonomic dysfunction had significantlylower physical work capacity at heart rate of 170 min⁻¹ than those with normal autonomic function or non-diabetic subjects (0.81 ± 0.12 vs 1.49 ± 0.16 and 1.54 ± 0.20 W kg⁻¹ p = 0.01). Physical work capacity at heart rate of 170 min⁻¹ was related to glycated haemoglobin level (r = −0.55, p = 0.01), to resting heart rate (r = 0.57, p =0.01), and to deep breathing heart rate variation (r = 0.51, p = 0.02). In conclusion, impaired work capacity is associated with poor blood glucose control and cardiovascular autonomic dysfunction. Autonomic tests can help to identify those patients who may need special consideration during exercise.     

The Role of Plasma Non-esterified Fatty Acids During Exercise in Type 2 Diabetes Mellitus

Elevated fasting plasma non-esterified fatty acid (NEFA) levels have been reported in Type 2 diabetes. We examined whether such changes persist during low-grade exercise and influence carbohydrate metabolism. Eight Type 2 diabetic patients with moderate glycaemic control and eight healthy controls received the anti-lipolytic agent, acipimox, or placebo on separate occasions before exercising for 45 min at 35 % pre-determined V_o2max. Fasting plasma NEFA levels were similar (0.40 ± 0.06 (SEM) and 0.45 ± 0.05 mmol l^?1; healthy and Type 2 diabetic subjects) following placebo, and increased to comparable levels with exercise (0.73 ± 0.07 and 0.73 ± 0.10 mmol l^?1). Acipimox lowered basal NEFA levels (0.14 ± 0.03 and 0.28 ± 0.04 mmol I^?1; both p < 0.05 vs placebo), and prevented the rise with exercise. Blood glucose (p < 0.001) and serum insulin (p < 0.01) levels were higher in the Type 2 diabetic patients (vs controls) for both treatments. Whole body lipid oxidation increased from baseline to a comparable degree with exercise following placebo (3.2 ± 0.3 and 2.8 ± 0.3 mg kg^?1 min^?1; healthy and Type 2 diabetic subjects, both p < 0.02). Although less marked, the same was also observed following acipimox (2.0 ± 0.4 and 2.1 ± 0.5 mg kg^?1 min^?1; both p < 0.05). Carbohydrate oxidation increased with exercise in both subject groups, but with no significant difference between the treatments. Thus, the metabolic response to low-grade exercise was normal in Type 2 diabetic patients with moderate glycaemic control, but occurred against a background of hyperinsulinaemia. Plasma NEFA do not exert a major regulatory effect on carbohydrate metabolism during low-grade exercise.     

The Splanchnic Circulation and Postural Hypotension in Diabetic Autonomic Neuropathy

Postural hypotension results from sympathetic failure to cause superior peripheral vasoconstriction. The importance of the splanchnic circulation was studied by measuring mesenteric artery blood flow with duplex Doppler scanning. Nine normal and 9 Type 1 diabetic controls were compared to 8 Type 1 patients with autonomic neuropathy whose pressure fell 40–113 mmHg (range) on tilting. Measurements were made supine and after vertical tilt, fasting without insulin and after a 550 kcal meal. Superior mesenteric artery diameter decreased on tilting in normal controls but not in diabetic control or neuropathy groups (supine vs tilted: controls. 6.3 ± 0.9 to 5 ± 0.9 mm, p = 0.004, diabetic controls: 6.0 ± 0.6 to 6.0 ± 1.0 mm, and neuropathy group: 6.4 ± 0.9 to 5.6 ± 0.9 mm), but proportional blood flow changes were similar in all subjects (controls: 407 ± 154 to 255 ± 67 ml min^?1 (-31%, p = 0.03), diabetic controls: 379 ± 140 to 306 ± 149 ml min^?1 (-8%, p = 0.28), neuropathy group: 639 ± 371 to 435 ± 142 ml min^?1 (-23%, p = 0.10). Postprandially supine superior mesenteric artery flow increased in all subjects but this did not affect the degree of systolic blood pressure drop on tilting (fasting vs postprandial blood flow: controls: 407 ± 154 to 775 ± 400 ml min^?1 (p = 0.04), diabetic controls: 379 ± 140 to 691 ± 262 ml min^?1 (p = 0.01), neuropathy group: 639 ± 371 to 943 ± 468 ml min^?1 (p < 0.06)). The similarity of superior mesenteric artery responses to tilting in the three groups, and the lack of exacerbation of postural hypotension in the presence of postprandial hyperaemia indicates that control of splanchnic blood flow is less important in the aetiology of diabetic autonomic postural hypotension than previously thought.     

Inhibition of glucose production and stimulation of bile flow by R (+)‐α‐lipoic acid enantiomer in rat liver

Abstract: Aims/Background: R (+)‐α‐lipoic acid (RLA) has been suggested for the treatment of liver diseases, but has also been shown to improve glucose utilization in diabetic patients. Because detailed information of RLA action on carbohydrate metabolism in intact liver is lacking, we examined concentration‐dependent effects of RLA on hepatic glucose production. Methods: RLA (10^?6?10^?3 mol L^?1) or buffer (control) was infused in isolated livers of fasted rats during recirculating perfusion for 90 min (n = 4–6/group). Hepatic glucose and lactate fluxes and bile secretion were continuously monitored. Results: RLA reduced lactate (10 mmol L^?1)‐dependent glucose production in concentration‐dependent fashion (R = ? 0.780, P < 0.001) by up to 67% compared with control (0.36 ± 0.02 µmol min^?1 g^?1). In parallel, RLA dose dependently decreased lactate uptake (R = ? 0.592, P < 0.001) also by up to 67% (control: 0.58 ± 0.08 µmol min^?1 g^?1). RLA (10^?4 mol L^?1 and 10^?3 mol L^?1) stimulated bile flow by ～ 20 and ～ 50%, respectively (P < 0.02 vs. control). After 10^?3 mol L^?1 RLA infusion, liver glycogen was ～ 3 fold higher (5.2 ± 1.1 vs. control: 1.8 ± 0.2 µmol g^?1, P < 0.002). Also at low lactate concentrations (1 mmol L^?1), 10^?3 mol L^?1 RLA reduced glucose production by ～ 53% and lactate uptake by ～ 60%, but stimulated bile secretion by ～ 50% (P < 0.05). Conclusion: RLA reduces hepatic glucose release by inhibiting lactate‐dependent glucose production in a concentration‐dependent fashion.     

Insulin sensitivity in alcoholics in a withdrawal state

Abstract. Insulin sensitivity in non-diabetic alcoholics in a withdrawal state was investigated using a euglycaemic clamp technique on two occasions with an interval of 1 week. Insulin was infused at a rate of 40 mU m^?2 min^?1 (n = 9) and 20 mU m^?2 min^?1 (n = 9). Hepatic glucose production was estimated with tritiated glucose in six subjects. The fasting glucose level at the first examination, 5.1 ± 0.2 mmol l^?1 exceeded that found at the second examination, 4.7 ± 0.1 mmol l^?1 (P < 0.05), although the C-peptide concentration was higher at the first examination (2.7 ± 0.3 vs. 1.6 ± 0.2 ng ml^?1: P < 0.001). Both glucose uptake (5.0 ± 0.6 vs 6.2 ± 0.7 mg kg^?1 min^?1: P < 0.05) and tissue sensitivity (M/I; 0.08 ± 0.02 vs. 0.1 ± 0.02 mg kg^?1 min^?1/mU l^?1; P < 0.05) increased between the first and second euglycaemic clamp (40 mU m^?2 min^?1). At the low insulin infusion rate (20 mU m^?2 min^?1), the tissue sensitivity to insulin increased (0.09 ± 0.01 vs. 0.13 ± 0.02 mg kg^?1 min^?1/mU l^?1; P < 0.05). Hepatic glucose production did not change during the examination period (2.2 ± 0.2 vs. 2.3 ± 0.1 mg kg^?1 min^?1), neither was there a change in the suppression of hepatic glucose output during hyperinsulinaemia (40 mU m^?2 min^?1). Our findings indicate that, in non-diabetic alcoholics, insulin sensitivity in peripheral tissues is decreased during the early part of a withdrawal period.     

QT Interval Length and Diabetic Autonomic Neuropathy

QT interval length was measured in ECG recordings from three groups of age-matched male subjects: 36 normal subjects, 41 diabetic patients without (DAN-ve), and 34 with (DAN+ve) autonomic neuropathy. ECG samples were selected from previously recorded 24-h ECGs on the basis of a clearly defined T wave and a steady RR interval over 2 min of around 750 ms (80 beats min^?1). There were no significant differences in RR interval between the groups. The two diabetic groups had slightly longer QT measurements (normal 365 ± 14 (±SD) ms, DAN-ve 373 ± 18 ms, DAN+ve 375 ± 23 ms, p = 0.05), and corrected QT (QTc) values (normal 423 ± 15 ms, DAN-ve 430 ± 20 ms, DAN+ve 435 ± 24 ms, p = 0.05). Ten diabetic patients fell above our defined upper limit of normal for QTc (>mean + 2SD). There was a significant correlation in the DAN-ve group between the QT indices and 24-h RR counts (QT r = ?0.38, p < 0.01; QTc r = ?0.40, p < 0.01). We conclude that there are some small alterations in QT interval length in the steady state in diabetic autonomic neuropathy. The changes appear to be due to autonomic impairment, rather than diabetes per se.     

Physiological,Symptomatic and Hormonal Responses to Acute Hypoglycaemia in Type 1 Diabetic Patients with Autonomic Neuropathy

The effects of peripheral autonomic neuropathy on the symptomatic, physiological, and hormonal responses to acute insulin-induced hypoglycaemia were studied in two groups of patients with Type 1 diabetes, matched for age, duration of diabetes, and prevailing glycaemic control. A group of eight patients who gave a history of normal awareness of hypoglycaemia and had normal cardiovascular autonomic function tests were compared to a group of six patients who had symptoms of autonomic dysfunction and gross abnormalities of cardiovascular autonomic function tests. An additional two patients with autonomic neuropathy who also had hypoglycaemia unawareness were studied. Acute hypoglycaemia was induced by intravenous infusion of insulin (2.5 ***mU kg^?1 min^?1) and the onset of the acute autonomic reaction (R) was identified objectively by the sudden rise in heart rate and onset of sweating. Cognitive function and hypoglycaemia symptom scores were estimated serially, and plasma counterregulatory hormones were measured. Acute autonomic activation was observed to occur in all subjects in response to hypoglycaemia and commenced at similar venous plasma glucose concentrations in both groups (neuropathic patients: 1.6 ± 0.2 mmol I^?1 vs non-neuropathic patients 1.6 ± 0.2 mmol I^?1, p = 0.9,). In the neuropathic patients plasma adrenaline responses were significantly lower at all time points from time R until time R + 30 min (MANOVA for repeated measures, F = 19.4, p < 0.001). The total autonomic symptom score at R was slightly lower in the neuropathic patients (12 (8–12) median (range)) but was not significantly different from the non-neuropathic patients (14 (10–26), p = 0.10), and the total neuroglycopenic symptom scores were very similar (neuropathic group: 11 (6–21) vs non-neuropathic group: 11.5 (6–22), p = 0.95). Although some of the autonomic responses were lower, but not significantly so, in the patients with autonomic neuropathy this study suggests that peripheral autonomic neuropathy is not the principal cause of hypoglycaemia unawareness in patients with Type 1 diabetes.     

Modulation of Glucose and Growth Hormone Responses to Meals and Exercise in Type 1 Diabetes by Cholinergic Muscarinic Blockade

Anticholinergic drugs suppress nocturnal and exercise-related growth hormone (GH) secretion in Type 1 diabetes; nocturnal GH suppression is associated with a fall in fasting plasma glucose levels. The aim of this study was to assess the effect of GH suppression on glucose levels following a period of meals and exercise in physiological pattern. Six Type 1 diabetic men recruited from the outpatient clinic were studied in random order at least 1 week apart. After an overnight fast subjects received two-thirds of their usual subcutaneous insulin and either 200 mg oral pirenzepine or placebo at time 0 min. Between 90 and 120 min subjects exercised continuously on an ergometric cycle. Standard meals or snacks were eaten at 30, 150, 270, and 390 min. Venous blood was collected from an indwelling cannula between 0 and 570 min. The mean incremental rise in plasma glucose after breakfast (δ peak/_{90 min}) was 2.6 ± 0.5 (mean ±SEM mmol l^?1 (pirenzepine) vs 4.5 ± 0.8 (placebo)), p < 0.05. Following exercise the fall in plasma glucose (δ gluc_{90–240 min}) was 6.4 ± 1.9 (pirenzepine) vs 2.0 ± 1.3 (placebo), p < 0.005. The exercise-related peak rise in GH was 12.6 ± 3.3 (pirenzepine) vs 28.5 ± 6.0 mU l^?1 (placebo), p = 0.08. Excluding one outlying result there was an inverse correlation between the integrated exercise-related increase in GH between 90 and 240 min and the fall in glucose over the corresponding time period (n = 11, r = ?0.75, p = 0.008). In conclusion suppression of exercise-related GH secretion by pirenzepine is associated with a subsequent lowering of plasma glucose levels. The smaller post-prandial glucose rise pre-exercise implies also a direct effect of pirenzepine on meal-related glucose tolerance in Type 1 diabetes.     

Urinary Excretion and Clearance of Insulin in Diabetic and Normal Children and Adolescents

Seventy-two diabetic (38 males) and 86 normal (41 males) children provided timed overnight urine collections. Fourteen of the diabetic and 33 of the normal children had concurrent overnight plasma insulin profiles. Urinary insulin clearance in the diabetic subjects was compared with excretion of albumin, growth hormone, retinol-binding protein, and N-acetyl-β-D -glucosaminidase. In the normal subjects, urinary insulin excretion correlated with mean overnight plasma levels in the boys (r = 0.82, p< 0.001) but not in the girls (r = 0.32), and varied with puberty stage in the boys. Insulin clearance was greater in boys than girls during puberty, and fell in both sexes with advancing puberty. Insulin excretion was greater in diabetic than normal children in both sexes at all puberty stages. Insulin clearance was also greater in diabetic than normal subjects (1.05 ± 0.1 ml min^?1 1.73 m^?2 vs o.48 ± 0.05 ml min^?1 1.73 m^?2, p< 0.001). Insulin excretion as a percentage of the filtered load was also greater in diabetic than normal subjects (1.9 ± 0.27% vs 0.85 ±0.09%, p < 0.01). In the diabetic children, there was a correlation between urinary insulin and growth hormone excretion (r = 0.52, p < 0.02), and retinol-binding protein in those (n = 10) with higher retinol binding protein excretion (r = 0.76, p = 0.01). The value of urinary insulin excretion as a measure of free plasma insulin levels in normal and diabetic children may be limited by sex differences in renal insulin clearance, and by proximal renal tubular dysfunction in children with diabetes.     

Improved carbohydrate metabolism after physical training and dietary intervention in individuals with the 'atherothrombogenic syndrome'. Oslo Diet and Exercise Study (ODES). A randomized trial

Objectives. To compare the single and joint effect of 1-year diet and exercise intervention on carbohydrate metabolism and associated coronary risk variables. Design. Unmasked, randomized, 2×2 factorial intervention trial with 1-year duration for each participant. Setting. The participants were recruited from a screening examination of 40-year-old persons in Oslo, Norway. Subjects. Two hundred and nineteen sedentary men and women, with diastolic blood pressure 86–99 mmHg, HDL cholesterol <1.20 mmol L^-1, triglycerides >1.4 mmol L^-1, total cholesterol 5.20–7.74 mmol L^-1 and BMI>24. Participants were randomly allocated to control (n=43), diet (n= 55), exercise (n=54) and diet+exercise (n=67). Interventions. Exercise: supervised endurance exercise three times a week. Diet: reduce weight, increase the intake of fish and reduce total fat intake. Main outcome measures. One-year changes in insulin and glucose before and after a standardized glucose load. Results. As compared with controls fasting insulin in pmol L^-1 decreased significantly in the combined diet and exercise group (3.9±6.2 versus -22.6±4.7 respectively, P=0.003). Insulin in pmol L^-1 after glucose load decreased significantly in all intervention groups compared to controls (diet: -82.2± 49.9 P=0.02; exercise: -92.4±60.1 P=0.03; diet+exercise: -179.6±45.1 P=0.0004). Fasting glucose in mmol L^-1 decreased significantly in the diet alone group (0.21±0.07 P=0.006) and in the diet+exercise group (-0.26±0.08 P=0.005). In a subgroup analysis of the good responders, the observed changes with respect to total cholesterol (-0.76 mmol L^-1), HDL cholesterol (0.16 mmol L^-1), triglycerides (-0.72 mmol L^-1), systolic and diastolic blood pressure (-8.5/-6.8 mmHg) were all statistically significant compared to the control with P<0.001. Conclusions. Exercise and diet intervention and in particular the combination of the two, were effective in improving carbohydrate metabolism. Associated risk factors were also affected in a beneficial direction.     

Changes in autonomic nervous function during the 4-year follow-up in middle-aged diabetic and nondiabetic subjects initially free of coronary heart disease

Objectives. To study the changes in autonomic nervous function during the 4-year follow-up period in diabetic patients and to investigate factors predicting autonomic nervous dysfunction Design. A 4-year follow-up study. Setting. At baseline the study subjects without known cardiovascular disease were recruited from a large group of diabetic and nondiabetic subjects selected randomly from a baseline population. Subjects. Middle-aged control subjects (n=44), patients with insulin-dependent diabetes mellitus (n=32) and patients with non-insulin-dependent diabetes mellitus (n=32) were studied at baseline and after the 4-year follow-up. Interventions. Autonomic nervous function tests and exercise test at baseline and after the 4-year follow-up. Results. At the baseline, heart rate variation during deep breathing was significantly lower in patients with insulin-dependent diabetes (13.0±1.2 beats min^?1; P<0.05) and in patients with non-insulin-dependent diabetes (12.9±1.5 beats min^?1; P<0.05) than in control subjects (16.6±1.1 beats min^?1). At baseline, autonomic nervous function score was significantly higher indicating disturbed autonomic nervous function in patients with insulin-dependent diabetes (1.74±0.19; P<0.01) than in control subjects (1.24±0.14), but the difference was not significant between control subjects and patients with non-insulin-dependent diabetes (1.47±0.12). During the follow-up, autonomic nervous function score increased in patients with noninsulin-dependent diabetes to 2.00±0.21 (P<0.001, as compared to baseline), but did not change in patients with insulin-dependent diabetes (1.77±0.18) or control subjects (1.22±0.12). In both diabetic groups, the deterioration of autonomic nervous function score during the 4-year follow-up was associated with poor glycaemic control at baseline. Clinical manifestation of coronary heart disease was found in three (7%) control subjects, 12 (37%; P<0.001) patients with insulin-dependent diabetes and 11 (34%; P<0.01) patients with non-insulin-dependent diabetes mellitus at follow-up examination. Autonomic nervous function was more abnormal in those insulin-dependent diabetic patients with coronary heart disease than those without. Conclusions. During the 4-year follow-up the impairment in autonomic nervous function occurred mainly in patients with noninsulin-dependent diabetes. Poor glycaemic control appears to be an important determinant of the progression of autonomic nervous dysfunction in diabetes.     

Excessively high soluble Klotho in patients with acromegaly

Abstract. Sze L, Bernays RL, Zwimpfer C, Wiesli P, Brändle M, Schmid C (Division of Endocrinology and Diabetes, University Hospital, Zurich; Division of Endocrinology and Diabetes, Kantonsspital, Gallen; Department of Neurosurgery, University Hospital, Zurich; and Department of Internal Medicine, Kantonsspital Frauenfeld, Frauenfeld, Switzerland). Excessively high soluble Klotho in patients with acromegaly. J Intern Med 2012; 272 : 93–97. Objectives. Klotho‐deficient mice develop a syndrome resembling accelerated ageing, and genetic variants of Klotho have been associated with human ageing. In humans, serum levels of soluble Klotho decrease with age and with chronic renal failure. The aim of our study was to examine the relationship between excess growth hormone (GH) and serum levels of Klotho in patients with acromegaly, a disease usually caused by a pituitary adenoma, which is associated with high phosphate levels and reduced life expectancy. Patients and design. We determined the levels of soluble Klotho, GH and insulin‐like growth factor 1 (IGF‐1) in serum samples from 24 consecutive patients with acromegaly (nine women/15 men, age 28–76 years) before and after transsphenoidal surgery. Results. Soluble Klotho levels were excessively high at baseline (mean ± SEM, 4.2 ± 0.7 ng mL^?1) and correlated with GH (r = 0.64), IGF‐1 (r = 0.57) and tumour size (r = 0.5). In multiple regression analysis, soluble Klotho was associated with GH after correction for age, gender and levels of creatinine and phosphate (P = 0.029). After surgery, GH and IGF‐1 levels decreased in all patients (from 26.3 ± 5.2 to 2.6 ± 0.6 μg L^?1, P <0.0001, and from 588 ± 35 to 193 ± 12 μg L^?1, P < 0.001, 0.0001, respectively). Creatinine increased from 71 ± 3 to 80 ± 3 μmol L^?1 (P < 0.001), and phosphate decreased from 1.37 ± 0.04 to 1.06 ± 0.02 mmol L^?1 (P < 0.001). The markedly increased preoperative levels of soluble Klotho returned towards normal after surgery (0.7 ± 0.1 ng mL^?1, P < 0.0001). Conclusions. This is the first study to show dramatically increased soluble Klotho levels in an acquired disease in humans. Reversal following tumour removal suggests a causal relation between the GH‐producing adenoma and high serum Klotho concentration in acromegaly.     

Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study

Abstract. Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, Lambrecht L, Paul L (Vrije Universiteit Brussel, Brussels; Artesis University College Antwerp, Antwerp; University Hospital Brussels, Brussels; Private Practice For Internal Medicine, Ghent/Aalst; CVS Contactgroep, Bruges; Belgium; and University of Glasgow, Glasgow, UK). Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome. J Intern Med 2010; 268 : 265–278. Objectives. To examine the efficacy of the pain inhibitory systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) during two different types of exercise and to examine whether the (mal)functioning of pain inhibitory systems is associated with symptom increases following exercise. Design. A controlled experimental study. Setting and subjects. Twenty‐two women with ME/CFS and 22 healthy sedentary controls were studied at the Department of Human Physiology, Vrije Universiteit Brussel. Interventions. All subjects performed a submaximal exercise test and a self‐paced, physiologically limited exercise test on a cycle ergometer. The exercise tests were undertaken with continuous cardiorespiratory monitoring. Before and after the exercise bouts, subjects filled out questionnaires to assess health status, and underwent pressure pain threshold measurements. Throughout the study, subjects’ activity levels were assessed using accelerometry. Results. In patients with ME/CFS, pain thresholds decreased following both types of exercise, whereas they increased in healthy subjects. This was accompanied by a worsening of the ME/CFS symptom complex post‐exercise. Decreased pressure thresholds during submaximal exercise were associated with postexertional fatigue in the ME/CFS group (r = 0.454; P = 0.034). Conclusions. These observations indicate the presence of abnormal central pain processing during exercise in patients with ME/CFS and demonstrate that both submaximal exercise and self‐paced, physiologically limited exercise trigger postexertional malaise in these patients. Further study is required to identify specific modes and intensity of exercise that can be performed in people with ME/CFS without exacerbating symptoms.     

Sex differences in essential hypertension

Abstract. A group of 41-year-old hypertensive men (n = 35, blood pressure (BP) 149.9 ± 2.1/ 98.9 ± 1.1 mmHg, mean ± SEM) who had never received treatment for their condition were compared with hypertensive women of the same age (n = 18, BP 155.9 ± 4.3/ 98.1 ± 1.6 mmHg) with comparable body mass index (BMI. 25.9 ± 0.5 vs. 24.9 ± 4.5 kg m^?2) who, also, had never received treatment. The lipid profile was more atherogenic in the men, with lower HDL cholesterol (1.21 ± 0.04 vs. 1.38 ± 0.06 mmol l^?1 P = 0.04), higher total cholesterol (6.04 ± 0.14 vs. 5.54 ± 0.18 mmol l^?1. P = 0.04) and triglycerides (1.80 ± 0.16 vs. 0.96 ± 0.10 mmol l^?1, P < 0.001). The hypertensive men had higher haemoglobin (P < 0.001) and haematocrit. Plasma catecholamines were inversely related to BMI in the women only (r = ?0.52, P < 0.05 for both noradrenaline and adrenaline). Women with BMI above 25 kg m^?2 had significantly lower arterial plasma adrenaline and noradrenaline than those with BMI below 25 kg m^?2 (28 ± 5 vs. 78 ± 16 pg ml^?1, P < 0.01 and 101 ± 17 vs. 206 ± 33 pg ml^?1, P < 0.01 respectively). A negative curvelinear relationship appeared between arterial adrenaline and insulin (r = 0.49, P= 0.05). These results suggest a male propensity for athero-thrombogenic risk factors in otherwise comparable hypertensive subjects. A close relationship between metabolic risk factors within the normal range seems to exist even in hypertensive women. The decreased sympathetic activity at rest in the obese hypertensive women indicates different pathophysiological mechanism for hypertension in lean and obese. Decreased sympathetic activity and thus reduced energy expenditure, promotes a risk for weight gain, and could explain the inverse relationship between insulin and adrenaline.     

Forearm Substrate Exchange during Hyperinsulinaemic Hypoglycaemia in Normal Man

To assess muscle substrate exchange during hypoglycaemia, 8 healthy young male subjects were studied twice during 2 h of hyperinsulinaemic euglycaemia followed by 4 h of (1) hypoglycaemia (plasma glucose < 2.8 mmol l^?1), and (2) euglycaemia. Insulin was infused at a rate of 1.5 mU kg^?1 min^?1 throughout. When compared to euglycaemia, hypoglycaemia was associated with: (1) increment in circulating glucagon (65 ± 8 vs 23 ± 4 ng l^?1, p < 0.05), growth hormone (19.9 ± 3.6 vs 2.6 ± 1.3 μg l^?1, p < 0.05), adrenaline (410 ± 88 vs 126 ± 32 ng l^?1, p < 0.05) and increased suppression of C-peptide (0.5 ± 0.1 vs 1.0 ± 0.1 μg l^?1, p < 0.05) along with a modest lowering of insulin (103 ± 10 vs 130 ± 13 mU l^?1, p < 0.05); (b) decrease in plasma glucose level (3.0 ± 0.07 vs 5.0 ± 0.12 mmol l^?1 p < 0.05), forearm glucose uptake (0.21 ± 0.09 vs 1.21 ± 0.21 mmol l^?1, p < 0.05) and requirement for exogenous glucose (5.6 ± 1.1 vs 13.2 ± 0.9 mg kg^?1 min^?1 p < 0.005) together with an impaired suppression of isotopically determined endogenous glucose production (0.34 ± 0.5 vs ?2.3 ± 0.3 mg kg^?1 min^?1, p < 0.05); (3) exaggerated increase in blood lactate (1680 ± 171 vs 1315 ± 108 μmol l^?1, p < 0.05) and a decrease in alanine (215 ± 18 vs 262 ± 19 μmol l^?1, p < 0.05). Forearm release of lactate (130 ± 43 vs 12 ± 31 μmol l^?1, p = 0.09) tended to be increased, whereas alanine balance (18 ± 6 vs 17 ± 5 μmol l^?1) was unchanged. (4) Total forearm blood flow increased similarly during both studies (4.4 ± 0.6 vs 4.2 ± 0.5 ml 100 ml^?1 min^?1). These data suggest that the human forearm is not a major site for glucose uptake nor for lactate production during protracted hypoglycaemia; the fact that forearm glucose uptake is reduced sixfold during hypoglycaemia further suggests that restriction of glucose uptake in muscles plays a frontline role in the defence against hypoglycaemia.     

Symptoms,Hormones, and Glucose Fluxes During a Gradual Hypoglycaemia Induced by Intraperitoneal vs Venous Insulin Infusion in Type I Diabetes

Intraperitoneal (IP) insulin infusion with programmable implantable pumps is associated with a reduction in hypoglycaemic events when compared to intensive diabetes management with subcutaneous insulin in patients with Type 1 diabetes mellitus. The mechanism may involve more physiological insulin kinetics, lower peripheral insulin levels or a specific hepatic action of portal insulin on hypoglycaemic counter regulation. To investigate the latter two hypotheses, we performed two hypoglycaemic clamps (controlled blood glucose decrement to 2.2 mmol l^?1) in random order in 12 Type 1 diabetic patients. Insulin was infused either IP or IV for 150 min, at rates chosen to generate similar peripheral insulin levels (1 mU/kg^?1 min^?1 IV or 2 mU/kg^?1 min^?1 IP, n = 6) to evaluate direct hepatic action, or at similar rates (1 mU/kg^?1 min^?1 IV and IP, n = 6) to evaluate IP indirect effects via lower peripheral insulinaemia. Hepatic glucose production and glucose utilization were measured by [6, 6 ²H] glucose dilution technique. Glucose production was lower (1.7 ± 0.4 vs 0.5 ± 0.4 mg kg^?1min^?1, p < 0.05), and utilization was similar at the end of the matched-insulinaemia IV and IP clamps, respectively. By contrast, glucose production was higher (1.7 ± 0.5 IV vs 2.7 ± 0.3 IP mg kg^?1 min^?1, p < 0.01) and glucose utilization lower (4.4 ± 1.0 IV vs 3.3 ± 0.2 IP mg kg^?1 min^?1, p < 0.05) with IP delivery at the end of the matched-dose clamps. Counterregulatory hormones and hypoglycaemic symptoms increased similarly in all clamps. In summary, IP insulin, when compared to IV insulin at similar delivery rates, but not at similar insulinaemia, is associated with a less negative glucose balance (glucose production-glucose utilization) during hypoglycaemia. Such a mechanism may play a role in the reduced hypoglycaemic risk seen with IP implantable pumps.     

Preservation of Renal Haemodynamic Response to an Oral Protein Load in Non-insulin-dependent Diabetes Mellitus

Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) were determined, for 2h prior to and 3h following the ingestion of a 1.2 g kg^?1 meat meal, in seven normotensive normoalbuminuric Type 2 diabetic patients exhibiting good glycaemic control (fasting plasma glucose (mean ± SD): 7.2 ± 2.0 mmol l^?1; glycosylated haemoglobin: 8.1 ± 1.7%) and in nine normal subjects selected for similar basal GFR values. Baseline GFR and ERPF (corrected to 1.73 m² surface area) were 83 ± 10 and 410 ± 76 ml min^?1 for the Type 2 diabetic patients and 86 ± 11 and 405 ± 113 ml min^?1 for the normals. GFR increased by 38 ± 8 and 32 ± 15% in the diabetic patients and normals, to 108 ± 25 and 105 ± 26 ml min^?1 (p < 0.01 vs baseline). Peak ERPF was 501 ± 127 and 476 ± 119 ml min^?1 for the two respective groups (p < 0.01 vs baseline). Filtration fractions at peak GFR and EPRF values were unchanged from baseline for either groups. Fractional clearance of albumin for the Type 2 diabetic patients was unaltered by protein ingestion. Therefore, protein ingestion in Type 2 diabetes, as in normals, results in an acute elevation of GFR. Absolute and incremental changes in GFR were identical for the two groups. These data demonstrate a preserved capacity for renal vasodilatation in Type 2 diabetic patients despite their greater chronological age.     

Lipoprotein lipase gene variants and progression of nephropathy in hypercholesterolaemic patients with type 2 diabetes

Objective. Recent prospective studies have identified hyperlipidaemia as an independent determinant of diabetic nephropathy. Lipoprotein lipase (LPL) is a key enzyme in the postprandial processing of triglycerides and VLDL. Among a number of common sequence variants of the LPL, HindIII has been associated with coronary heart disease and, more recently, with microalbuminuria in type 2 diabetes. We evaluated the progression of renal disease in hypercholesterolaemic type 2 diabetic patients in relation to this polymorphism. Design and subjects. We followed up for 4 years 65 consecutively enrolled microalbuminuric patients with type 2 diabetes; of whom 28 had hypercholesterolaemia (6.62 ± 0.9 mmol L^?1, group A) and 37 were normocholesterolaemic (4.68 ± 0.5 mmol L^?1, group B). Main outcome measures. After performing the genetic analyses, albumin excretion rate (AER) and estimated glomerular filtration rate (GFR), calculated by the simplified equation of the MDRD Study Group, were repeated every year. Results. In group A, AER increased more (?AER: 11 [38] vs. 4 [18] μg min^?1 per year in group B, P < 0.0001) while GFR declined faster (?3.5 ± 2.1 vs. ?2.0 ± 1.4 mL min^?1 per year, P < 0.02). Patients homozygous for the allele + of HindIII showed a significantly faster decline of GFR and a higher increase of AER (both P = 0.0001) even after adjustment for cholesterol levels and anthropometric variables. Conclusions. In hypercholesterolaemic type 2 diabetic patients with microalbuminuria, the renal disease has an accelerated course, particularly in those carrying the H₊/H₊ genotype of the HindIII polymorphism at the LPL locus.     

Alanine turnover in the postabsorptive state and during parenteral hyperalimentation before and after surgery

Influence of total parenteral nutrition and operation on alanine turnover and venous alanine concentration was determined in 5 patients with stomach carcinoma using single injection technique of U-¹⁴C alanine. Every patient served as his own control. In the postabsorptive state alanine turnover was 1.63 ± 0.31 mgatC · min^?1, not different from a control group (1.84 ± 0.60 mgatC · min^?1); during total parenteral nutrition alanine turnover increased to 3.21 ± 0.5g mgatC · min^?1 with a rise in alanine concentration from 0.96 ± 0.17 mgatC · L^?1 +0.69 ± 0.22 mgatC · L^?1. After surgery during the same total parenteral nutrition alanine turnover increased further to 3.78 ± 0.17 mgatC · min^?1 with a lowering of alanine concentration to 1.44 ± 0.22 mgatC · L^?1. The present results show the distinct influence of TPH on alanine kinetics. The present data indicate that alanine turnover cannot be deduced from blood alanine concentration.     

Hyperglycaemic Progression in Subjects with Impaired Glucose Tolerance: Association with Decline in Beta Cell Function

Impaired glucose tolerance is associated with an increased risk of Type 2 diabetes. This prospective cohort study has examined the variables associated with hyperglycaemic progression in order to elucidate the aetiology of this deterioration. The 5 mg glucose-kg ideal body weight-min^?1 continuous infusion of glucose with model assessment (CIGMA) test was used to quantitate glucose tolerance, beta cell function, and insulin sensitivity. Twenty-two Caucasian subjects who had impaired glucose tolerance identified on two separate tests underwent repeat testing after a median period of 24 months. At follow-up, 2 of the 22 subjects (9%) had Type 2 diabetes, 18 (82%) had impaired glucose tolerance, and 2 (9%) were normoglycaemic. The fasting and achieved (60-min) glucose levels were significantly higher at follow-up (mean ± SD) (5.7 ± 0.8 vs 5.5 ± 0.5 mmol l^?1, p = 0.029 and 10.0 ± 0.9 vs 9.6 ± 0.6 mmol l^?1, p = 0.021, respectively), and beta cell function was significantly lower (median and interquartile range): 75% (50–93%) vs 90% (70–135%), p = 0.009. The changes in fasting plasma glucose were found to correlate with change in body mass index (r_s = 0.46, p = 0.03). We conclude that impaired glucose tolerance is associated with decline in beta cell function, and denotes substantial risk of hyperglycaemic progression. Randomized controlled trials are warranted to determine whether exercise programmes, dietary advice, and attentive follow-up and effective preventive strategies for subjects with impaired glucose tolerance.