Journal of internal medicine. Supplement最新文献

Resistance to insulin-stimulated glucose uptake is a common phenomenon, occurring in approximately 25% of the population at large, and is associated with a number of conditions known to be risk factors for coronary heart disease (CHD). These include hyperinsulinaemia, abnormal glucose tolerance, non-insulin-dependent diabetes mellitus, increased plasma triglyceride and decreased high-density-lipoprotein cholesterol concentrations, smaller, denser low-density-lipoprotein particles, hypertension, and abnormalities of fibrinolysis. These abnormalities frequently occur in a cluster within individuals. Understanding the basis of these changes, as well as the interrelationships between them, will contribute substantially to future studies of the causes of CHD, and ultimately form the basis for the clinical management of insulin-resistant individuals.

Cardiovascular disease is two to three times more common in diabetic patients than in the non-diabetic population. Although risk factors that affect the general population such as age, cigarette smoking, hypertension, obesity and hypercholesterolaemia also affect diabetic subjects, the increased prevalence of hypertension and obesity in non-insulin-dependent diabetes mellitus (NIDDM) only partially explains the increased morbidity and mortality from coronary heart disease (CHD). Other factors must therefore be considered in this group of patients. Triglyceride concentrations, particularly post-prandial levels, may be important. Diabetic subjects have increased very-low-density-lipoprotein (VLDL), increased intermediate-density-lipoprotein (IDL) and low high-density-lipoprotein (HDL) concentrations, and differences in lipoprotein composition may partly explain increased atherogenesis. Although LDL levels of diabetic patients are not different from those of control subjects. LDL particles are potentially atherogenic as they are smaller, more dense and prone to oxidative modification. NIDDM subjects also have altered apolipoprotein concentrations, including increased apoB, apoC-III, and decreased apoA-I; in addition, apoE-2 may be over-represented in diabetic populations. Thus, apart from the traditional risk factors, there are several lipoprotein compositional abnormalities that may contribute to the increased prevalence of CHD in diabetes.

In a randomized, double-blind study, in which recombinant tissue plasminogen activator (rt-PA) administered at an early stage was compared with placebo in patients with suspected acute myocardial infarction (AMI), the effects on pain were studied in 312 patients. Inclusion criteria were as follows: (a) chest pain of duration less than 2 h and 45 min; and (b) age less than 75 years. Chest pain was estimated subjectively by the patients, using a 10-point numerical rating scale, at hourly intervals for the first 24 h, and by the requirement for narcotic analgesics. Compared with placebo, rt-PA treatment resulted in a 43% reduction in mean total pain score (P less than 0.0001), a 26% reduction in pain duration (P less than 0.01), and a 33% reduction in morphine requirement (P = 0.01). Fifty-seven per cent of all patients developed a confirmed AMI. In these subjects rt-PA reduced the pain score by 46% (P less than 0.001). Among patients without confirmed AMI, a 37% reduction in pain score was observed (P = 0.05). The effect on pain was most marked in patients with ST-elevation on the initial ECG. We conclude that early treatment with rt-PA in suspected AMI reduces chest pain considerably. The effect is most marked in patients with ST-elevation on the initial ECG.

Insulin regulates cellular metabolic reactions by its action on the plasma membrane, intracellular enzymes and the nucleus. The first stage in the propagation of the insulin signal is the coupling of insulin to specific receptors at the cell surface. The exact mechanism whereby the transmembrane signalling mechanism (s) results in different insulin-mediated cellular effects is not known. However, the insulin receptor tyrosine kinase, the expression of second messengers, and the action of protein kinase C may, either individually or in combination, mediate some of the insulin effects, such as translocation and activation of glucose transporter proteins. Insulin resistance in clinical conditions such as insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), hypertension and obesity may be acquired to a large extent, and is thus partially reversible. Regulatory factors in insulin sensitivity, such as free fatty acids, counterregulatory hormones and blood glucose level, play an important role in the metabolic control and pathogenesis of insulin resistance in man.

The selective alpha 1-adrenoceptor-blocking agents constitute effective monotherapy in the control of essential hypertension. The failure of well-controlled trials of other antihypertensives to achieve the expected reduction in coronary heart disease has given rise to speculation that the antihypertensives used are atherogenic because of metabolic changes induced in the patient. The selective alpha 1-adrenoceptor blockers have positive effects on carbohydrate metabolism, hyperinsulinaemia and lipid metabolism. These changes, which consist of a modest reduction in total serum cholesterol, an increase in high-density-lipoprotein cholesterol, and a decrease in low-density lipoprotein, very-low-density lipoprotein and triglyceride, accompanied by a reduction in hyperglycaemia and serum insulin levels, have been observed in hypertensive patients. Experimental studies using isolated tissue culture and intact animal systems have confirmed these observations. The changes in metabolism may represent the key to prevention of coronary heart disease in the hypertensive population.

Insulin is the dominant glucoregulatory factor; by suppressing endogenous glucose production and stimulating glucose utilization, it lowers the plasma glucose concentration. Normally, feedback-regulated changes in insulin secretion play a key role in maintaining plasma glucose levels within a rather narrow range (approximately 4.0-7.0 mmol l-1) despite marked changes in glucose influx (e.g. following a meal, compared to fasting), efflux (e.g. during exercise), or both. Severe insulin deficiency causes insulin-dependent diabetes mellitus (IDDM), and substantial insulin excess causes hypoglycaemia. However, the regulation of systemic glucose balance normally involves a highly co-ordinated interplay between the glucose-lowering effects of insulin and the glucose-elevating actions of an array of glucose counterregulatory hormones, primarily glucagon (and epinephrine under some conditions). Thus there are redundant glucoregulatory factors, and a hierarchy exists among the latter. Although insulin stands at the top of that hierarchy, glucoregulation is not achieved by insulin alone. This is emphasized by the glycaemic chaos of IDDM, with wide swings from hyperglycaemia to hypoglycaemia. The latter is not exclusively the result of the intermittent hyperinsulinaemia inherent in imperfect insulin replacement therapy. Deficient glucagon and epinephrine secretory responses occur, and are now known to increase the risk of iatrogenic hypoglycaemia. However, insulin is generally the dominant glucoregulatory hormone under physiological conditions. The glucose counterregulatory hormones approach parity with insulin only when plasma glucose concentrations are lowered to levels that threaten brain function.

Independent trials of early administration of beta-blockers and thrombolytic agents have shown beneficial effects on both short- and long-term prognoses in acute myocardial infarction (AMI). The effects of a combination of the two strategies have not been thoroughly documented. Three hundred and fifty-two patients, of less than 75 years of age, with chest pain indicative of AMI, and onset less than 2 h and 45 min before first examination, were randomized to treatment with rt-PA or placebo. All patients without contraindication were given intravenous metoprolol 15 mg acutely and then 200 mg orally daily. Treatment was started either at the prehospital stage or in hospital. Thirty-seven per cent of patients had contraindications to beta-blockade, the most frequent of which were heart rate less than 60 beats min-1 and hypotension. The remaining 63% were given intravenous beta-blockade. No side-effects of metoprolol, alone or in combination with rt-PA, were observed during the prehospital phase. Overall, toleration of the treatment was good. Reduction in enzymatically estimated infarct size by rt-PA was more pronounced in patients who were also treated with metoprolol (41%, P less than 0.001) than in those with contraindications to beta-blockade (15%, NS). Patients who were also treated with metoprolol also had a lower incidence of Q-wave infarctions, congestive heart failure and ventricular fibrillation than those who were not given intravenous beta-blockade. In conclusion, toleration of intravenous administration of rt-PA and metoprolol was good, and this was also the case in the prehospital phase.(ABSTRACT TRUNCATED AT 250 WORDS)

In insulin-dependent diabetes mellitus, an excess frequency of raised blood pressure occurs in association with increased urinary albumin excretion. It is not known whether the renal disorder causes the raised blood pressure, or whether the two disorders occur concomitantly. In non-insulin-dependent diabetes mellitus, any excess of raised blood pressure is small or non-existent when adjustments are made for obesity. However, raised blood pressure is found in glucose-intolerant individuals, independent of obesity. Reported associations between albumin excretion and blood pressure in non-insulin-dependent diabetes are inconsistent.

It has been suggested that the failure of thiazide therapy, administered to treat high blood pressure, to prevent coronary heart disease is related to the metabolic adverse effects of these drugs. The almost consistent observation of reduced serum potassium and total body potassium associated with diuretics appears to be of clinical importance. It may cause not only an increased risk of cardiac arrhythmias but also impaired glucose tolerance and abnormal lipid metabolism, while replacement of potassium has been shown to eliminate the risk of arrhythmias as well as thiazide-induced hyperglycaemia. The effect of the thiazide-induced short-term changes in serum lipids is unclear. Present experience suggests that thiazide-induced impairment of glucose tolerance is due to both reduced glucose-stimulated insulin release and increased peripheral resistance to the action of insulin. The blunted initial response of the pancreatic beta-cells to glucose is clearly dependent on serum potassium, and may cause postprandial hyperglycaemia during most of the day and night. This hypothesis is supported by the observation of enhanced glucose and insulin levels after an overnight fast, as well as 60-120 min after glucose challenges. Increased average levels of insulin may eventually cause down-regulation of cellular insulin receptors, i.e. insulin resistance. It is also conceivable that elevated insulin levels may cause hypertriglyceridaemia and possibly other abnormalities of lipid metabolism. Some recent observations indicate that the prognosis in treated hypertensive patients improves if both blood pressure and cholesterol levels are successfully controlled. We therefore emphasize the importance of normalizing serum potassium when using diuretic-based therapies in the treatment of hypertension.