The Effect of Spironolactone on Lipid,Glucose and Uric Acid Levels in Blood during Long-Term Administration to Hypertensives

Spironolactone, an aldosterone antagonist, was given in a daily dose of 100 mg to 15 patients with primary hypertension for one year. Fasting levels of lipids, uric acid, glucose, insulin, potassium and growth hormone were measured before and after 6 and 12 months of treatment. Total cholesterol, LDL cholesterol, glucose, potassium and growth hormone were unchanged, HDL cholesterol fell from (mean±SD) 1.5±0.6 to 1.1 ±0.3 mmol/l (p<0.05) after 6 months of treatment and remained lowered (1.0 ±0.3 mmol/l) (p<0.01) after 12 months of treatment. There was a transient fall after 6 months of treatment in triglycerides from 2.4±1.5 to 2.0±1.1 mmol/l (p < 0.05), uric acid from 380±73 to 342±58 μmol/l (p<0.05) and an increase in insulin from 16±9.5 to 28.6±26.8 mU/l (p<0.05). The blood glucose curves above fasting levels after glucose loading were unchanged during spironolactone treatment, whereas the area under the net insulin curve was higher after 6 months of treatment (163±103 mU · h/l) than before treatment (105±71 mU·h/l), indicating a small and transient insulin resistance. Thus, spironolactone impaired the glucose tolerance transiently and gave small and almost transient changes in fasting serum lipid and uric acid levels.     

Blood flow is an important determinant of forearm glucose uptake following a mixed meal

Abstract. Insulin-mediated vasodilation has been suggested to be of importance for glucose uptake during normoglycemic hyperinsulinemia. If this also is valid after an ordinary mixed meal remains to be evaluated. Forearm blood flow (FBF) and forearm glucose uptake change (evaluated by venous occlusion plethysmography) and glucose arteriovenous differences were evaluated over 120 minutes in 10 healthy volunteers following an ordinary mixed meal (700–900 kcal, 34% of energy from fat). Fasting arterial glucose level was 4.9±0.9 mmol/l, and the maximum glucose level was reached 30 minutes after the start of ingestion (6.6±0.8 mmol/l, p<0.0001). Plasma insulin levels were increased four-fold. FBF increased rapidly within 20 minutes after the start of ingestion and reached its maximum after 50 minutes (94% higher than baseline level, p<0.01). After 2 hours FBF was still substantially elevated (75% above baseline level, p<0.01). Forearm glucose uptake increased fivefold already after 20 minutes (p<0.01). During the 2 hours, the increase in FBF contributed to 41% of the forearm glucose uptake (p<0.05). The present study showed that the increase in FBF seen after an ordinary mixed meal is important for the change in forearm glucose uptake. These results support the view that modulation of limb blood flow is a determinant of glucose uptake.     

Intramuscular triglyceride content is increased in IDDM

Summary 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, HbA_{1 c} 7.7 ± 0.3 %, insulin dose 48 ± 3 U/day). Insulin sensitivity was measured with a 4 h euglycaemic (5 mmol/l) hyperinsulinaemic (1.5 mU or 9 pmol · kg^–1· 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. [Diabetologia (1998) 41: 111–115] Received: 12 June 1997 and in revised form: 8 September 1997     

Cardiocirculatory and myocardial energetic effects of prostaglandin E1 in severe left ventricular failure due to chronic coronary heart disease

The cardiocirculatory actions of brief (69 ± 5 minutes) infusions of prostaglandin E₁ were evaluated in nine chronic coronary heart disease patients with severe left ventricular (LV) failure caused by previous myocardial infarction. Prostaglandin E₁ infusion did not alter heart rate (HR) and produced modest declines in mean systemic blood pressure (BP) (85 ± 6 to 76 ± 5 mm Hg, p < 0.025) and LV filling pressure (19 ± 3 to 15 ± 2 mm Hg, p < 0.01). Simultaneously, prostaglandin E₁ augmented LV pump function raising cardiac index from 1.9 ± 0.2 to 2.5 ± 0.2 L/min/m² (p < 0.005), elevating stroke index from 28 ± 2.4 to 35 ± 2.9 ml/beat/m² (p < 0.01), and increasing stroke work index from 26 ± 4.3 to 30 ± 4.4 gm·m/m² (p < 0.02). Additionally, total systemic vascular resistance decreased from 1862 ± 192 to 1282 ± 100 dynes-sec-cm^?5 (p < 0.02) and double product LV aerobic index of HR · systolic BP diminished from 9492 ± 666 to 8278 ± 493 (p < 0.02). Concomitantly, in the forearm, vascular resistance fell, blood flow rose, and venous tone remained unchanged. These results indicate that prostaglandin E₁ is a potent systemic arteriolar dilator with markedly beneficial effects on cardiac function in chronic coronary patients having severe ischemic LV failure refractory to conventional therapy.     

The relationship of glycaemic level to advanced glycation end-product (AGE) accumulation and retinal pathology in the spontaneous diabetic hamster

Summary To assess the relationship between glucose and advanced glycation end products (AGE) and the relationship between AGE and retinal changes in vivo, we studied the time course of retinopathy over 12 months in trypsin digest preparations and measured glycaemia and retinal AGE in spontaneous diabetic hamsters of mild (MD) and severe (SD) phenotypes. Blood glucose levels were elevated in MD (9.44 ± 0.76 mmol/l) and in SD (3 months: 24.3 ± 1.4 mmol/l; 12 months: 31.7 ± 0.8 mmol/l) over non-diabetic controls (NC: 7.15 ± 0.25 mmol/l; p < 0.05 or less vs MD; p < 0.001 vs SD). Similar relations were found for HbA₁. Retinal AGE in mild diabetes was 405 ± 11.3 arbitrary units (AU) (NC 245 ± 7.7; p < 0.01) after 3 months and remained unchanged. A non-linear increase of AGE over time was found in severe hyperglycaemic hamsters (466 ± 21 AU after 3 months and 758 ± 21 AU after 12 months; p < 0.001 vs MD). Pericyte loss in mild diabetes progressed from –26 % after 3 months to –41 % after 12 months (p < 0.001 vs NC). Whereas the initial pericyte loss in severely diabetic hamsters was identical to the mildly diabetic group, a higher degree of pericyte loss occurred after 12 months (–57 %; p < 0.05 vs MD). Endothelial cell numbers remained unaffected by mild hyperglycaemia, but significantly increased over time in severe diabetes reaching 31.7 % above controls after 12 months (p < 0.001 vs NC and MD). Microaneurysms were absent in all retinae examined. Acellular capillary segments were increased in mild diabetes (3.83 ± 0.31 per mm² of retinal area) and severe diabetes (7.83 ± 0.73) over controls (1.0 ± 0.23). These data suggest that a threshold of glycaemia might exist above which AGE removal systems become saturated. Pericyte loss and acellular capillary formation are associated with mild increases in blood glucose and AGE levels while endothelial cell proliferation requires higher glucose and AGE levels. [Diabetologia (1998) 41: 165–170] Received: 31 July 1997 and in revised form: 29 September 1997     

Alcohol and the Heart

To evaluate the hemodynamic changes related to alcohol flush, the effects of ethanol intake (0.5 g/kg) were studied by echocardiography and systolic time intervals in 10 Finnish and 9 Japanese healthy volunteers. In 5 Japanese subjects, post-drink facial flush was associated with elevated blood acetaldehyde (peak levels 20–83 μmol/l) and marked cardiocirculatory stimulation. Heart rate was increased directly post ingestion by 65% (p<0.01), stroke index by 23% (p<0.05), and cardiac index by 106% (p<0.05). Diastolic blood pressure was simultaneously decreased by 23% (p<0.05), peripheral vascular resistance by 54% (p<0.01), and circumferential wall stress by 22% (p<0.05); ejection fraction was raised by 26% (p<0.01). The other Japanese and the Finnish subjects had no detectable acetaldehyde in blood after ethanol ingestion. The average hemodynamic alterations in them were similar in direction to the changes presented above, but quantitatively 6–10 times smaller (p<0.005 for each of these variables). Thus, in Orientals with genetically defective acetaldehyde oxidation, ingestion of even small amounts of alcohol evokes intense enhancement of left ventricular function, probably because of acetaldehyde-induced catecholamine release and peripheral vasodilation.     

Impaired Left Ventricular Filling in Young Female Diabetics

ABSTRACT To assess left ventricular (LV) function in diabetes mellitus, M-mode echocardiograms were recorded in 36 insulin-treated diabetic women, mean age 25±6 (SD) years, and 13 healthy women of the same age. Echocardiographic tracings of the septum and LV posterior wall were digitized and continuous plots were made of LV dimension and its rate of change. The pattern of LV filling was abnormal in 19 diabetics, when the mean value ±2 SD in the healthy women was taken as the normal range of the indices. The most common abnormality was a prolonged rapid filling period. The LV systolic function was normal in all diabetics. Diabetics with severe microvascular complications had thicker LV walls (p<0.05) and smaller LV end-diastolic diameters and stroke volumes (p<0.01) than the healthy women. The electrocardiographic voltage was lower in the diabetic group (p<0.05). These studies suggest that minor abnormalities in LV function reflecting stiffness of the myocardium are common in young female diabetics, a patient group with a relatively low prevalence of coronary artery disease.     

Diastolic heart function in RA patients

The results of some epidemiological studies point to the presence of an increased risk of cardiovascular disease (CVD), particularly atherosclerosis and congestive heart failure (CHF) in rheumatoid arthritis (RA). At least 50% of abnormalities remained asymptomatic. Pathological conditions contributing to myocardial dysfunction such as high serum levels of IL-6, C-reactive protein (CRP) and TNF alpha are present both in RA and CHF patients. The most common pathological mechanism leading to the development of heart failure is left ventricular (LV) diastolic dysfunction, which remains clinically asymptomatic for a long time. The aim of this study was to assess the systolic and diastolic functions of the LV in RA patients without clinically evident cardiovascular disease, using pulsed Doppler echocardiography. Our purpose was also to estimate whether there is a correlation between the duration and severity of RA and the degree of LV diastolic dysfunction. A comparison of the average values of echocardiographic measurements was made between the RA group and control group, which constituted healthy volunteers. Left ventricular mass index in RA group was significantly greater than in the control group (105.2 ± 32.6 vs. 87.9 ± 16.8; p < 0.05) so were the interventricular septum end-diastolic thickness (1.01 ± 0.33 vs. 0.86 ± 0.12; p < 0.05), the LV posterior wall end-diastolic thickness (0.94 ± 0.08 vs. 0.83 ± 0.11; p < 0.0001) and the aortic root diameter (3.18 ± 0.31 vs. 3.10 ± 0.63, p < 0.001). The ejection fraction in RA group was significantly lower than in the control group (64.4 ± 1.3 vs. 66.3 ± 1.3; p < 0.0001). The assessment of diastolic function parameters revealed significantly longer isovolumetrc relaxation time (IVRT) and shorter deceleration time (DT) in RA patients compared to the control group. Patients in stage II or III revealed significantly lower LV mass index (99 ± 17 vs. 131 ± 42; p < 0.05) and the interventricular septum end-diastolic thickness (0.94 ± 0.10 vs. 1.28 ± 0.5; p < 0.05) than those in stage IV. Mean aortic diameter was significantly greater in individuals in stages III and IV (3.73 ± 0.28) than in the stage II of the disease (2.77 ± 0.21), p < 0.05. No differences in echocardiographic parameters’ values were observed between seropositive, seronegative, nodule-present and nodule-absent persons. Echocardiographic examination revealed valvular heart disease in 24 (80%) RA and 6 (20%) control patients (p < 0.0001).     

Intermittent high glucose enhances cell growth and collagen synthesis in cultured human tubulointerstitial cells

Aims/hypothesis. We investigated the effects of constant and intermittently increased glucose concentrations on human proximal tubule cells and cortical fibroblasts in primary culture. Methods. Cells were grown to confluence and then exposed for 4 days to 6.1 mmol/l d-glucose (normal), 25 mmol/l d-glucose (high), or 6.1 mmol/l alternating with 25 mmol/l d-glucose on a daily basis. Results. In proximal tubular cells, exposure to high glucose caused an 11 % increase in thymidine uptake (p < 0.05), a 230 % increase in secretion of transforming growth factor beta 1 (TGF-β1; p < 0.05) and a 393 % increase in platelet derived growth factor. Intermittent exposure to high glucose caused thymidine uptake to further increase by 42 % (p < 0.01) and TGF-β1 secretion by 352 % (p < 0.01) but no additional increase in platelet-derived growth factor secretion was observed. Cellular protein content increased by 27 % (p < 0.05) and collagen synthesis by 29 % (p < 0.05), changes that were not observed in cells constantly exposed to high glucose. In cortical fibroblasts constant exposure to high glucose caused a 35 % increase in thymidine uptake (p < 0.01). Intermittently high glucose increased thymidine incorporation a further 58 % (p < 0.001), collagen synthesis by 65 % (p < 0.01) and insulin-like growth factor binding protein 3 secretion by 216 % (p < 0.01). Conclusion/interpretation. In cultured human tubulointerstitial cells, increased glucose concentrations change cell growth, collagen synthesis and cytokine secretion. These effects are enhanced following intermittent exposure to high glucose, indicating that short lived excursions in glycaemic control have important pathological effects on the human tubulointerstitium. [Diabetologia (1999) 42: 1113–1119] Received: 18 January 1999 and in revised form: 3 March 1999     

Effect of Correction of Hyperglycemia on Left Ventricular Function in Non-Insulin-Dependent (Type 2) Diabetics

ABSTRACT Systolic time intervals (STI) were recorded in 33 newly diagnosed non-insulin-dependent diabetics (19 men, 14 women, aged 44–64 years) before and after 3–8 months' dietary therapy. The mean (±SD) fasting blood glucose was 11.1±2.6 mmol/l before treatment and 7.8±1.8 at the second examination (p<0.001). Concomitantly with the decline in blood glucose concentration, the heart rate corrected pre-ejection period (PEP) decreased from 139±11.9 to 135±14.4 msec (mean±SD) (p<0.05), the heart rate corrected left ventricular ejection time (LVET) increased from 400 ± 15.1 to 410±20.7 msec (p<0.0025) and the PEP/LVET ratio decreased from 0.39±0.06 to 0.36±0.06 (p<0.005). When the diabetics were divided into two groups according to the degree of the decline in blood glucose concentration, only those whose fasting blood glucose decreased by ≥3 mmol/l showed significant changes in STI. No significant changes were observed in the mean heart rate or systolic blood pressure during the treatment. Cardiac dysfunction occurring in untreated non-insulin-dependent diabetics may be caused by metabolic factors and it may be reversed at least partially by correction of hyperglycemia.     

Incidence of Nocturnal Hypoglycaemia in Insulin-dependent Diabetic Patients on Intensive Therapy

ABSTRACT The frequency of nocturnal hypoglycaemia, i.e. blood glucose concentration (BG) <3.0 mmol/l, was evaluated in consecutively selected insulin-dependent patients on multiple insulin injections (MII), n =23, or continuous subcutaneous insulin infusions (CSII), n =25. Blood was sampled hourly from 23.00 to 07.00. Seven patients (30%) on MII had at least one BG <3.0 mmol/l during the night. Eleven patients (44%) on CSII had hypoglycaemia (NS). The total number of BGs <3.0 mmol/l was higher on CSII, 42 of 225, versus 16 of 207 on MII (p<0.025). The duration of hypoglycaemia was 2 hours (range 1–6) on MII and 4 hours (range 1–7) on CSII with a maximal prevalence at 4 hours and between 5 and 7 hours, respectively (p=<0.05). The frequency of nocturnal hypoglycaemia is high in patients on intensified insulin regimens. Nocturnal hypoglycaemia occurs later in the night and is of longer duration on CSII than on MIL HbA_1c, BG before bedtime and in the morning might be useful in the evaluation of nocturnal hypoglycaemia.     

Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans

Aims/hypothesis Diabetic dyslipidaemia contributes to the excess morbidity and mortality in patients with type 2 diabetes. Exogenous glucagon-like peptide 1 (GLP-1) lowers postprandial glycaemia predominantly by slowing gastric emptying. Therefore, the effects of GLP-1 on postprandial lipid levels and gastric emptying were assessed. Methods 14 healthy male volunteers were studied with an i.v. infusion of GLP-1 (1.2 pmol kg⁻¹ min⁻¹) or placebo over 390 min in the fasting state. A solid test meal was served and gastric emptying was determined using a ¹³C-labelled sodium octanoate breath test. Venous blood was drawn frequently for measurement of glucose, insulin, C-peptide, glucagon, GLP-1, triglycerides and NEFA. Results GLP-1 administration lowered fasting and postprandial glycaemia (p<0.0001). Gastric emptying was delayed by GLP-1 compared with placebo (p<0.0001). During GLP-1 administration, insulin secretory responses were higher in the fasting state but lower after meal ingestion. After meal ingestion, triglyceride plasma levels increased by 0.33±0.14 mmol/l in the placebo experiments (p<0.0001). In contrast, the postprandial increase in triglyceride levels was completely abolished by GLP-1 (change in triglycerides, −0.023±0.045 mmol/l; p<0.05). During GLP-1 infusion, plasma concentrations of NEFA were suppressed by 39% in the fasting state (p<0.01) and by 31±5% after meal ingestion (p<0.01). Conclusions/interpretation GLP-1 improves postprandial lipidaemia, presumably as a result of delayed gastric emptying and insulin-mediated inhibition of lipolysis. Thus, by lowering both glucose and lipid concentrations, GLP-1 administration may reduce the cardiovascular risk in patients with type 2 diabetes.     

Modulation of Nitric Oxide Synthase Activity in Brain,Liver, and Blood Vessels of Spontaneously Hypertensive Rats by Ascorbic Acid: Protection from Free Radical Injury

End organ damage in essential hypertension has been linked to increased oxygen free radical generation, reduced antioxidant defense, and/or attenuation of nitric oxide synthase (NOS) activity. Ascorbic acid (AA), a water-soluble antioxidant, has been reported as a strong defense against free radicals in both aqueous and nonaqueous environment. In this study we examined the hypothesis that antioxidant ascorbic acid may confer protection from increased free radical activity in brain, liver, and blood vessels of spontaneously hypertensive rats (SHR). Male SHRs were divided into groups: SHR + AA (treated with AA, 1 mg/rat/day; for 12 weeks) or SHR (untreated). Wister-Kyoto rats (WKY) served as the control. Mean systolic blood pressure (SBP) in treated and untreated SHR was 145 ± 7 mmHg and 142 ± 8 mmHg, respectively. AA treatment prevented the increase in systolic blood pressure in SHR by 37 ± 1% (p < 0.05). NOS activity in the brain, liver, and blood vessels of WKY rat was 1.82 ± 0.02, 0.14 ± 0.003, and 1.54 ± 0.06 pmol citruline/mg protein, respectively. In SHR, total NOS activity was significantly reduced by 52 ± 1%, 21 ± 3%, and 44 ± 4%, respectively. AA increased NOS activity in brain, liver, and blood vessels of SHR from 0.87 ±.03, 0.11 ±.01, and 0.87 ±.08 pmol citruline/mg protein to 0.93 ± 0.01, 0.13 ± 0.001, and 1.11 ± 0.03 pmol citruline/mg protein (p < 0.05), respectively. Lipid peroxides in the brain, liver, and blood vessels from WKY rats were 0.87 ± 0.06, 0.11 ± 0.005, and 0.47 ± 0.04 nmol MDA equiv/mg protein, respectively. In SHR, lipid peroxides in brain, liver, and blood vessels were significantly increased by 40 ± 3%, 64 ± 3%, and 104 ± 13%, respectively. AA reduced lipid peroxidation in liver and blood vessels by 17 ± 1% and 34 ± 3% but not in brain. Plasma lipid peroxides were almost doubled in SHR (p < 0.01) together with a reduction in total antioxidant status (6 ± 0.1%; p < 0.05), nitrite (53 ± 2%; p < 0.05) and superoxide dismutase (SOD) activity (36 ± 2%; p < 0.05). AA treatment reduced plasma lipid peroxide (p < 0.001), and increased TAS (p < 0.001), nitrite (p < 0.001), and SOD activity (p < 0.001). From this study, we conclude that brain, liver, and blood vessels in SHR are susceptible to free radical injury, which reduces the availability of NO either by scavenging it or by reducing its production via inhibiting NOS. In addition, brain, liver, and blood vessels in SHR; may be protected by antioxidant, which improves total antioxidant status, and SOD thus may prevent high blood pressure and its complications.     

Effects of lidocaine on regional intraventricular conduction in patients with coronary artery disease

Studies of isolated heart muscle and canine models of myocardial ischemia have demonstrated that lidocaine slows conduction in abnormal but not in normal tissues. To determine lidocaine's effects on intraventricular conduction (IVENT) in patients with coronary artery disease (CAD), we studied this agent in seven patients following left anterior descending coronary artery (LAD) bypass surgery. Epicardial electrodes were placed on the right atrium, left ventricle (LV) in the distribution of the LAD, and on the right ventricle (RV). On postoperative day 7, lidocaine was administered as 100 mg bolus followed by 4 mg/minute infusion for 2 hours. At constant atrially paced rate, bipolar electrograms were recorded from the LV and RV for the 2 hours of infusion and for 2 hours after discontinuation of infusion. Conduction intervals were measured from the earliest onset of QRS in three simultaneously recorded surface ECG leads to the major deflection of the electrogram from each ventricle. At peak effect, with mean lidocaine level of 2.7 ± 0.5 mg/ml, lidocaine slowed LV conduction by a mean of 6 ± 1 msec (14 ± 2%) (p < 0.001) and in the RV by 1 ± 0.3 msec (4 ± 1%) (p < 0.01). QRS duration changed 1 ± 1 msec (1 ± 1%) (NS). The values returned to baseline within 2 hours after discontinuation of lidocaine infusion. The difference in lidocalne's effect between the diseased LV and the normal RV was significant (p < 0.001).     

Lowering fatty acids potentiates acute insulin response in first degree relatives of people with Type II diabetes

Summary Studies have shown that a high plasma non-esterified fatty acid concentration may inhibit glucose induced insulin secretion in vitro and in vivo. The effect of lowering the fatty acid concentration on the acute insulin response was investigated in first degree relatives of people with Type II diabetes in a double-blind, randomised, placebo-controlled trial. Fifty first degree relatives of people with Type II diabetes volunteered for the study. Twenty five were given acipimox (250 mg/day, four times daily) and 25 placebo. The group treated with acipimox had a lower 2-h plasma glucose concentration (6.1 ± 0.2 vs 7.7 ± 0.3 vs mmol/l, p < 0.01); better insulin-mediated glucose uptake (35.4 ± 0.5 vs 28.3 ± 0.4 μmol/kg fat free mass per min, p < 0.01), acute insulin response (68 ± 4.4 vs 46 ± 7.3 mU/l, p < 0.01) and respiratory quotient (0.81 ± 0.02 vs 0.77 ± 0.03, p < 0.05); and a rise in the plasma glucagon (164 ± 63 vs 134 ± 72 ng/l, p < 0.05), growth hormone (1.31 ± 0.13 vs 0.97 ± 0.21 μg/l, p < 0.03) and cortisol (325 ± 41 vs 284 ± 139 nmol/l, p < 0.05) concentrations. The difference in the acute insulin response persisted, even after adjustment for the 2-h plasma glucose concentration, insulin-mediated glucose uptake, the fasting plasma glucagon concentration and the growth hormone concentration (p < 0.05). In a subgroup of eight patients acipimox was compared with acipimox plus intralipid. The acute insulin response (44 ± 5.1 vs 71 ± 5.3 mU/l, p < 0.01) and the insulin-mediated glucose uptake (27.4 ± 0.4 vs 36.7 ± 0.5 μmol/kg fat free mass per min, p < 0.003) were lower with acipimox plus intralipid treatment than with acipimox alone. It is concluded that long term acipimox treatment lowers the plasma fasting free fatty acid concentration and improves the acute insulin response and the insulin mediated glucose uptake. [Diabetologia (1998) 41: 1127–1132] Received: 27 January 1998 and in final revised form 29 April 1998     

Quantification of Left Ventricular Wall Dysfunction by M-Mode Echocardiographic Mapping in Heart Failure Following Acute Myocardial Infarction

ABSTRACT Echocardiographic mapping was performed in 44 patients on arrival in hospital and day 2 following acute myocardial infarction (AMI). To evaluate left ventricular (LV) function the per cent deviation of the mean systolic wall velocity (PD-V) from the normal was measured from 16 LV segments. Adequate data were obtained from 89% of the segments. The number of hypokinetic segments was somewhat higher in anterior than inferior AMI, reaching significance (p<0.05) on day 2. Dyskinetic segments were also more common in patients with anterior infarction (p<0.001), who also had significantly higher enzyme maxima than patients with inferior AMI (p<0.01). Enzyme maxima correlated well with the sum of PD-V from all hypokinetic segments on day 1 (r = 0.79, p<0.01). Compensatory hyperkinesia was more common in inferior than anterior AMI (p<0.001). Global LV function, estimated by subtracting the number of hyper- from hypokinetic segments (score σ S: Adj), was significantly related to heart failure (Killip classification) (p<0.01) and the respiratory rate (r = 0.71, p<0.01) in the acute phase as well as to heart failure during the first post AMI month (New York Heart Association classification).     

The Effect of Sodium Depletion and Potassium Supplementation on Vasopressin,Renin and Catecholamines in Hypertensive Men

ABSTRACT Seventeen 50-year-old hypertensive men (157±4/110±2 mmHg, mean ± SE) were given low sodium diet for one week, which was supplemented with potassium the following week. The urinary Na⁺/K⁺ excretion ratio changed from 2:1 to 1:5 and 1:12, respectively, during dietary intervention. Arterial plasma vasopressin decreased by 3.4±1.7 ng/l (0.05>p<0.10) and urinary excretion of vasopressin was reduced by nearly 50% (p<0.001) during sodium depletion, while plasma noradrenaline increased by 38% (p<0.001) and plasma dopamine showed an increase by 58% (p<0.001). Plasma renin concentration increased four-fold during sodium depletion (p<0.001). With combined salt depletion and potassium supplementation, arterial plasma vasopressin decreased by 9.5±4.0 ng/l (p<0.05) compared to control. Urinary excretion of vasopressin together with plasma noradrenaline and dopamine were unchanged during the second week. The reduction of blood pressure was most marked during the first week (143±3/103±2 mmHg, p<0.05), but continued to fall also during the second week. Thus, during sodium restriction in middle-aged hypertensive men, blood pressure reduction occurs concomitantly with inhibited vasopressin release, despite enhanced renin and catecholamine release. Potassium supplementation during sodium restriction induces only minor changes in these variables.     

Stimulation of adipose tissue lipolysis following insulin-induced hypoglycaemia: evidence of increased beta-adrenoceptor-mediated lipolytic response in IDDM

Summary The adrenergic regulation of adipose tissue lipolysis in response to insulin-induced hypoglycaemia (intravenous infusion of soluble insulin 0.10 IU · kg body weight⁻¹· h⁻¹ until the arterial plasma glucose fell below 2.8 mmol/l) was investigated directly in vivo in 11 insulin-dependent diabetic (IDDM) patients and 12 control subjects, using microdialysis of the extracellular space of abdominal subcutaneous adipose tissue. The tissue glycerol level (lipolysis index) and the escape of ethanol from the perfusion medium (blood flow index) were continuously monitored. During insulin infusion the arterial glucose level was reduced in parallel and the hypoglycaemic nadir was almost identical in the two groups (diabetic patients 2.2 ± 0.1 and control subjects 2.3 ± 0.1 mmol/l). While the maximum response of plasma epinephrine to hypoglycaemia was 30 % lower in diabetic patients than in the control subjects (p < 0.05), the glycerol levels in adipose tissue and in plasma, as well as in serum non-esterified fatty acids, increased twice as much in the former as in the latter group following hypoglycaemia (p < 0.01). Addition of the beta-adrenoceptor blocker propranolol (10⁻⁴ mol/l) to the tissue perfusate almost completely prevented the hypoglycaemia-induced increase in the adipose tissue glycerol level in both groups, whereas in situ perfusion with 10⁻⁴ mol/l of the alpha-adrenoceptor blocker phentolamine resulted in an additional increase in the tissue glycerol levels; during alpha-blockade, the glycerol response to hypoglycaemia remained enhanced by threefold in the diabetic patients (p < 0.01). In both groups local adipose tissue blood flow increased transiently in a similar way after hypoglycaemia; the increase being inhibited by in situ beta-adrenoceptor blockade. We conclude that both alpha- and beta-adrenergic mechanisms regulate adipose tissue lipolysis in response to hypoglycaemia. In IDDM, lipolysis is markedly enhanced following hypoglycaemia, despite a reduced catecholamine secretory response, because of increased beta-adrenoceptor action in adipose tissue. [Diabetologia (1996) 39: 845–853] Received: 5 July 1995 and in final revised form: 4 March 1996     

Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of Type II diabetes

Summary Extracts of the creosote bush (Larrea tridentata, family Zygophyllaceae) have long been used as a folk remedy for Type II (non-insulin-dependent) diabetes by native Americans in southwestern North America. In this study we have evaluated the metabolic effects of masoprocol, a pure compound isolated from the creosote bush, in a rat model of Type II diabetes. Animals were fed a 20 % fat (by weight) diet for 2 weeks prior to intravenous injection with streptozotocin (STZ, 0.19 mmol/kg). Diabetic animals (glucose 16–33 mmol/l) were treated with vehicle, metformin (0.83 mmol/kg body weight) or masoprocol (0.83 mmol/kg body weight) twice a day for 4 days. Masoprocol treatment lowered glucose concentrations an average of 35 % compared with vehicle (14.2 ± 1.1 vs 21.7 ± 1.0 mmol/l, p < 0.001), a reduction similar to metformin treatment (12.8 ± 0.9 mmol/l), without any change in insulin concentration. Masoprocol treatment also lowered triglyceride concentrations 80 % compared with vehicle (1.0 ± 0.1 vs 4.8 ± 0.3 mmol/l, p < 0.001), a reduction far greater than following metformin treatment (3.6 ± 0.3 mmol/l). Non-esterified fatty acid and glycerol concentration were decreased by approximately 65 % by masoprocol compared with vehicle, a reduction approximately twice as great as seen with metformin (p < 0.001). The effect of masoprocol on in vivo insulin-mediated glucose disposal was evaluated by infusing fat-fed/STZ rats with glucose (0.22 mmol · kg · min^–1) and insulin (30 pmol · kg · min^–1) for 5 h. In response to the infusion, steady-state plasma glucose concentrations were reduced 30 % in masoprocol-treated animals compared with vehicle controls (p < 0.05) with no change noted in rats treated with metformin. The effect of masoprocol treatment was also tested in primary adipocytes isolated from normal animals. Adipocytes treated with masoprocol (30 μmol/l) had higher basal and insulin-stimulated glucose clearance than did adipocytes treated with vehicle (p < 0.05). These data show that masoprocol decreases both plasma glucose and triglyceride concentrations in fat-fed/STZ rats, presumably as a result of its ability to both increase glucose disposal and decrease lipolysis. [Diabetologia (1999) 42: 102–106] Received: 3 April 1998 and in final revised form: 21 August 1998     

Metabolic control in newly kidney transplanted insulin-dependent diabetics: Improvement by insulin pump treatment (CSII)

Management of glucose homeostasis in newly kidney transplanted insulin-dependent diabetic patients is difficult. To examine whether continuous subcutaneous insulin infusion (CSII) could reverse this problem, six consecutive kidney-transplanted Type I diabetic patients either proceeded with conventional insulin therapy (CIT) or were changed to CSII beginning on the third postoperative day. After a mean of 13 days, the insulin administration mode was changed from CIT to CSII (n=3) or from CSII to CIT (n=3), and continued for a further 15 days. Mean blood glucose calculated on the basis of four daily measurements (8.00, 12.00, 17.00, 22.00 h) during the study periods was significantly lower during CSII (8.0±0.4 mmol/l, mean±SEM) than on CIT (11.0±0.6 mmol/l; p<0.005). Moreover, the variability of blood glucose expressed as the M-value was lower during the pump treatment compared to CIT (p<0.001), while the number of blood glucose values below 3.0 mmol/l was similar (3.8 vs. 4.4%). Diurnal metabolic and hormonal profiles were twice determined on each regimen with 2 hourly sampling. Glycemic control was again found to be improved during CSII therapy as compared to CIT (p<0.01 or 0.05<p<0.10). Moreover, insulin pump treatment resulted in a significant reduction of two major intermediary metabolites, lactate and glycerol (p<0.05 and p<0.01, respectively). The improved metabolic state during CSII was probably due 1) to a more physiologic serum-free insulin pattern, which exhibited postprandial plasma peaks mimicking that of non-diabetic subjects; and 2) to an increased ability to combat varying insulin resistance post-transplantation. In conclusion, in newly kidney transplanted insulin-dependent diabetics, insulin pump therapy results in improved (almost normal) metabolic control compared to that achieved with CIT.