高胰岛素血症与高血压病

对２２例高血压病不伴糖尿病患者及１７例正常对照者行口服葡萄糖耐量试验（ＯＧＴＴ），同时测定血胰岛素、胆固醇、甘油三酯水平及红细胞膜钠一钾泵活性。结果显示原发性裔血压病患者有明显高脂血症、糖耐量异常及高胰岛素血症，这些变化符合Ｒｅａｖｅｎ提出的“×”综合征。统计学表明：在去除年龄、肥胖等因素影响后，舒张压（ＤＢＰ）和空腹、餐后３０ｍｉｎ胰岛素值及其曲线下面积（ＡＵＣ）仍呈正相关（Ｐ值均＜０．０３）；收缩压（ＳＢＰ）和ＤＢＰ都与钠一钾泵活性呈负相关（Ｐ值分别为＜００１、＜０．００１）；各期胰岛素值（０、３０、６０、１２０ｍｉｎ）及其ＡＵＣ与钠一钾泵活性亦均呈负相关（ｐ值均＜０．０５）。以上结果表明：胰岛素抵抗及其所致高胰岛素血症是导致“×”综合征的关键，也是促进原发性高血压病人冠心病发生与发展的因素之一，因而对高血压病人仅依靠有效降压治疗不一定能有效地控制冠心病的发生率，尚须对其高胰岛素血症予以控制。     

INSULIN SENSITIVITY AND 131I INSULIN METABOLISM IN JUVENILE-TYPE DIABETICS

1. The acute response of blood glucose levels to insulin, and the half-time of disappearance and degree of protein binding of ¹³¹I-labelled insulin as determined by electrophoresis, have been studied in 43 insulin-dependent diabetics with disease of long duration. Of the patients studied, 21 (50%) had a blood glucose response to insulin which was within normal limits. The remaining 22 patients were insensitive, showing both a delay in response and a significantly decreased rate of fall of blood glucose levels after insulin administration. 2. A weak correlation was observed between insulin sensitivity and both the half-time of disappearance and the degree of protein binding of radioactive insulin, but no relationship was found between any of these parameters and the somatic index, the degree of “brittleness” of individual patients, the dose of insulin required or the duration of diabetes. 3. It is proposed that there may be two populations of juvenile-type diabetics, one sensitive and one insensitive to the acute effects of insulin, which cannot adequately be explained by the effects of heterologous antibody formation on injected insulin.     

ACANTHOSIS NIGRICANS, HIRSUTISM, INSULIN RESISTANCE AND INSULIN RECEPTOR DEFECT

A 24-year-old negress with the triad of acanthosis nigricans, hirsutism associated with polycystic ovaries and insulin resistance is reported. Metabolic studies were done 3 years after a bilateral ovarian wedge resection. Partial remission of the hirsutism and return of menstrual cycles occurred after surgery. Extreme resistance to endogenous and exogenous insulin was observed. Three studies of insulin receptors on circulating red blood cells (RBC) showed abnormal inhibition-competition curves, characterized by increased percentage insulin binding at higher unlabelled insulin levels. Scatchard plots suggested an apparent increase in the number of low affinity receptors. Despite the changes in receptor-insulin interaction, the defect does not seem to explain the insulin resistance since binding of insulin to a target tissue (RBC) appeared to be quantitatively normal at physiological insulin levels, suggesting a simultaneous post receptor defect.     

HYPERINSULINAEMIA AND INSULIN RESISTANCE OF CIRRHOSIS: THE IMPORTANCE OF INSULIN HYPERSECRETION

The mechanism for the hyperinsulinaemia in cirrhosis was investigated using two different approaches. In the first study, the metabolic clearance rate of insulin was measured at steady state in 13 cirrhotic and 13 weight-matched control subjects. With comparable insulin infusion rates (1.00 +/- 0.19 versus 1.07 +/- 0.15 mU/kg/min), steady-state plasma insulin concentrations (104 +/- 25 versus 87 +/- 12 microU/ml; P greater than 0.5) and MCRIRI (13.6 +/- 1.6 versus 15.4 +/- 2.0 ml/kg/min; P greater than 0.5) were similar. In the second study, fasting and oral glucose stimulated C-peptide/insulin ratios were compared in 16 cirrhotic and 18 weight matched control subjects. Although fasting glucose levels were significantly higher in the cirrhotic groups, all values were in the normal range (5.5 +/- 0.3 versus 4.8 +/- 0.1 mmol/l, P less than 0.02). However, fasting insulin (0.171 +/- 0.02 versus 0.068 +/- 0.004 nmol/l) and C-peptide (1.02 +/- 0.13 versus 0.42 +/- 0.02 nmol/l) were strikingly higher (P less than 0.001) in cirrhotic subjects. On the other hand, fasting C-peptide/insulin ratios were not statistically different in the two groups (6.18 +/- 0.52 versus 6.77 +/- 0.46; P greater than 0.3). This suggests that beta cell hypersecretion was the principal cause of the fasting hyperinsulinaemia, rather than decreased insulin hepatic extraction. Following the glucose load in 13 of the control and seven of the cirrhotic group, the C-peptide/insulin ratio fell in both groups but was significantly lower in the cirrhotic compared to control subjects at 30, 60 and 120 min, consistent with possible impairment of hepatic insulin extraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

链脲佐菌素糖尿病大鼠的胰岛素受体结合、胰岛素介体释放和葡萄糖氧化

作者测定了链脲佐菌素引起的糖尿病大鼠脂肪细胞膜对胰岛素特异结合率、肝细胞膜胰岛素介体释放和脂肪细胞葡萄糖氧化。结果表明:(1)糖尿病大鼠脂肪细胞膜对胰岛素特异结合率较正常大鼠显著增加,其胰岛素受体亲和力没有改变,但受体数目增加;(2)大鼠肝细胞膜加胰岛素诱导时,糖尿病鼠肝膜释放的抑制腺苷酸环化酶活力的胰岛素介体量较正常大鼠显著减少;(3)在糖尿病大鼠,基础的和胰岛素刺激的脂肪细胞葡萄糖氧化较正常大鼠显著降低。提示胰岛素介体释放量减少可能是引起受体后胰岛素抵抗的原因之一。     

THE EFFECTS OF LONG TERM GLICLAZIDE ADMINISTRATION ON INSULIN SECRETION AND INSULIN SENSITIVITY

Gliclazide (80 mg bd) was administered to nine subjects with type 2 (non insulin dependent) diabetes inadequately controlled on diet only. Twenty-four hour glucose, insulin and c-peptide profiles were obtained before and after one week and four months of therapy. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp before and after four months of treatment. Twenty-four hour glucose levels were significantly lowered after one week and four months. Insulin secretion, as assessed by the areas under the insulin and c-peptide curves, was enhanced after one week. The increase was most noted during the day in response to meals. The enhancement was maintained after four months of treatment with the increase in the postabsorptive phase becoming significant. Glucose utilisation rate was significantly increased at four months. It is concluded that both acute and prolonged gliclazide therapy directly or indirectly 1) enhances both meal stimulated and post absorptive insulin secretion and 2) increases insulin sensitivity. The relative contribution of each to improved diabetic control has not been established. (Aust NZ J Med 1989; 19: 44–49.)     

非胰岛素依赖型糖尿病合并冠心病者的胰岛素抵抗

为了解非胰岛素依赖型糖尿病（ＮＩＤＤＭ）病人中胰岛素抵抗与冠心病的关系，对４０例ＮＩＤＤＭ合并冠心病的男病人与３６例未合并冠心病的ＮＩＤＤＭ男病人的血糖、胰岛素、胰岛素敏感性指数（ＩＳＩ）、血脂、载脂蛋白等进行比较，并对其与冠心病的关系进行多因素ｌｏｇｉｓｔｉｃ逐步回归分析，结果显示，ＮＩＤＤＭ病人中的ＩＳＩ与冠心病呈显著负相关（ＯＲ０．２３７，９５％可信区间０．０９０９～０．６１６７，Ｐ＝０．００３２），这种相关独立于年龄、肥胖、血压、血脂等心血管危险因素。提示胰岛素抵抗是非胰岛素依赖型糖尿病病人冠心病发病的独立危险因素。     

THE RELATIONSHIP OF ERYTHROCYTE INSULIN RECEPTORS TO RED CELL AGE AND TO MONOCYTE INSULIN RECEPTORS

This study examines the degree to which erythrocyte insulin receptors might be used instead of monocyte insulin receptors to assess overall insulin receptor status. Red blood cells from eight normal subjects were fractionated into older and younger populations by high speed centrifugation. Fractionated red cells (3·5 ± 10⁹/ml) were incubated with 0·14 ng/ml of ‘monoiodo’¹²⁵I-insulin for 2·5 h at 15°C. The high reticulocyte fractions (mean 2·1% reticulocytes) had greater insulin binding than the low reticulocyte fractions (mean 0·6%), ?9·0% compared with 6·0% specific binding, respectively. The difference (P > 0·05) appeared to be predominantly due to a greater number of high affinity sites per cell in the high reticulocyte fractions. Culture of high and low reticulocyte fractions, from both normal subjects and patients with high reticulocyte counts, in vitro for 2·5 days at 37°C, markedly reduced reticulocyte count and insulin binding of the high reticulocyte fractions, but produced little change in the low reticulocyte fractions. It appeared the reticulocytes had a ten- to twenty-fold increase in binding sites compared with erythrocytes. There is little degradation of insulin by intact erythrocytes or reticulocytes at 37°C, with a dissociation between insulin binding and insulin degradation. The large degradative capacity of haemolysed red cells implies that insulin receptor assays would be invalid in the presence of haemolysis. Monocyte and erythrocyte receptors were compared in the same blood samples from overnight fasted subjects, with a correlation between insulin binding (r = 0·62). The inexact correlation may be partly due to the non-homogeneous insulin binding of red cells, but correction for differences between reticulocyte content of the assayed red cells only increased the correlation to r = 0.67. Whilst the non-homogeneity of red cells means that erythrocyte binding must be interpreted with caution, we cannot exclude similar non-homogeneity of monocyte populations.     

RELATIONSHIP BETWEEN RESISTANCE TO INSULIN AND BODY WEIGHT

The relationship between increased body weight and resistance to insulin was studied in a group of 14 healthy men. The reduction in blood glucose and plasma free fatty acid (FFA) levels was measured during one-hour infusions of insulin given in doses which would lead to physiological concentrations of insulin in the plasma. A relationship could not be demonstrated between the blood glucose response and body weight. However, the FFA concentrations fell to lower levels in the leaner than in the heavier subjects, so that a highly significant direct relationship was found between body weight and the post-insulin plasma FFA concentration. The studies therefore show that, over a range of commonly encountered body weights, resistance to insulin develops with increasing fatness. The study also shows that the plasma FFA response to insulin is a more sensitive index of insulin resistance than the blood glucose response.     

ADIPOSE-CELL SIZE AND IMMUNOREACTIVE INSULIN LEVELS IN OBESE AND NORMAL-WEIGHT ADULTS

The relationship between adipose-cell size and plasma levels of immunoreactive insulin (I.R.I.) was studied in 73 normal and obese individuals and in 12 obese patients before and after weight reduction. A strong positive correlation was found between adipose-cell size and fasting I._R._I. in both groups. This relation exists despite the widely differing degrees of obesity (and, therefore, their probable different total carbohydrate intakes). It is suggested that the increased adipose-cell size seen in obesity could sensitise the pancreas to produce more insulin.     

COMPARISON BETWEEN THE PLASMA INSULIN AND GLUCOSE RESPONSES TO FIVE DIFFERENT INSULIN REGIMES IN DIABETIC PATIENTS

Diurnal plasma insulin and glucose concentrations were studied in six diabetic patients, each treated with five different insulin regimes. Subcutaneous soluble insulin was too slow and long acting for physiological replacement of the normal insulin response to meals, but the peak insulin levels were higher than the postprandial levels of normal subjects. Intramuscular insulin, though absorbed more quickly than subcutaneous insulin, was not clinically advantageous. Three rather than two injections of soluble insulin gave improved blood glucose control but two combined injections of short and medium acting insulins gave nearly as good results. A long acting insulin was needed to prevent raised plasma glucose levels overnight.     

GLUCAGON-STIMULATED PLASMA C-PEPTIDE AND INSULIN LEVELS IN ACTIVE AND NON-ACTIVE ACROMEGALICS

The glucagon-stimulated insulin and C-peptide release in patients with active acromegaly, cured acromegalic patients and healthy controls were studied. There was an elevation of the fasting insulin levels in active acromegalics and the fasting C-peptide levels in both patient groups. After i.v. injection of glucagon the insulin and C-peptide levels increased. The highest levels were recorded in active acromegalics, but cured patients also had higher levels than the control group. The insulin/C-peptide ratio was increased in active acromegalics in comparison with that found for inactive acromegalics and normal controls. In addition, the plasma half-lives (T1/2) of endogenous insulin and C-peptide were measured. It was found that the T1/2 for insulin was increased in active acromegalics only. From this study we conclude that even when the treatment of acromegaly is effective insulin and C-peptide secretion do not normalize due, probably, to increased synthesis and release upon stimulation of the pancreatic beta-cells. In active acromegaly the removal of insulin is probably also reduced.     

BASAL AND STIMULATED INSULIN LEVELS RISE WITH ADVANCING PUBERTY

We studied the effect of pubertal development on insulin secretion. Intravenous glucose tolerance tests were performed on 47 islet-cell antibody negative siblings of diabetic children and on 16 normal adults. Puberty was staged using Tanner's criteria and subjects were grouped as follows: I, stage 1 (n = 16); II, stages 2 and 3 (n = 15); III, stages 4 and 5 (n = 16); IV, adults (n = 16). Fasting insulin increased with advancing puberty (p = 0.59, P less than 0.001). The stimulated insulin response also rose with increasing pubertal development: for the 0-10 min insulin area, p = 0.46, P less than 0.001 and for the 10-60 min area, p = 0.68, P less than 0.001. There was a low positive correlation between insulin and age to 16 years but multiple regression analysis showed that this could be accounted for by puberty alone. Indeed prepubertal children and adults did not differ. There was no correlation between glucose (fasting and 0-60 min area) and puberty or age. These findings suggest that insulin resistance increases during puberty, and this may contribute to the frequency of presentation or worsening control of insulin dependent diabetes at this time.     

FACTORS GOVERNING INSULIN AND GLUCAGON RESPONSES DURING NORMAL MEALS

An experimental model is described which can be used to study substrate and hormone responses to normal meals administered in very near normal circumstances. After 500, 300 and 125 calorie meals, the relative proportion of fat or protein content did not influence the plasma glucose except for minor differences between the high protein-high fat meals. The insulin response to such meals was correlated positively with the increment in glucose but reduction of protein content below 8 g caused a significant reduction in the increment in plasma insulin per unit increase in plasma glucose. Alterations in protein content above 8 g made no difference. Fat content of the meal did not significantly alter the insulin response. No evidence was obtained for a major component of insulin release attributable to either bulk or pre-absorption phenomena such as sight or smell. It is concluded that a significant accentuation of the insulin response to meals is dependent on a minimum amount of protein and that this is probably mediated by one of the gastro-intestinal hormones. Glucagon release is dependent on protein and carbohydrate content of the meal and is independent of the fat content. There may also be an early stimulation of glucagon release, regardless of content, which may also be hormonally mediated.     

A COMPARATIVE DOUBLE-BLIND TRIAL OF THE EFFECTIVENESS AND ANTIGENICITY OF SEMISYNTHETIC HUMAN INSULIN AND PURIFIED PORCINE INSULIN IN NEWLY TREATED DIABETIC SUBJECTS

Abstract A double-blind comparative trial of the effectiveness and antigenicity of semisynthetic human insulin (Novo) and highly purified (Monocomponent) porcine insulin was performed over a 12 month period in 20 diabetic subjects newly treated with insulin. Human insulin was shown to be indistinguishable from porcine insulin of comparable purity with respect to plasma glucose and glycosylated hemoglobin levels and insulin dose requirements. Human insulin was no less antigenic than porcine insulin; significant IgG-associated insulin binding activity was detected in six of the ten patients in the human insulin treated group and four of the ten patients in the porcine insulin treated group. In all patients, the binding activity was of low capacity. No adverse reactions to human insulin were noted. It is concluded that semisynthetic human insulin, like purified porcine insulin, is safe and effective. Although there may be advantages for human insulin in the setting of insulin allergy, this study does not indicate that human insulin has advantages over purified porcine insulin with respect to elicitation of antibodies of the IgG class.     

38例高血压病患者血脂与胰岛素抵抗

对３８例高血压病（ＥＨ）患者及２４例正常人空腹血清胰岛素（Ｉｎｓ）、Ｃ肽（ＣＰ）、血糖（ＳＧ）、甘油三酯（ＴＧ）、总胆固醇（ＴＣ）、高密度脂蛋白胆固醇（ＨＤＬ－Ｃ）及载脂蛋白（Ａｐｏ）含量进行测定，并推算胰岛素敏感指数（ＩＳＩ）。结果ＥＨ组Ｉｎｓ、ＣＰ升高，但ＩＳＩ显著降低，表明ＥＨ患者存在胰岛素抵抗（ＩＲ）。同时伴有ＴＧ、ＴＣ、ＡｐｏＢ１００、脂蛋白（ａ）［ＬＰ（ａ）］升高，ＨＤＬ－Ｃ、ＡｐｏＡＩ降低。相关分析表明，ＥＨ患者Ｉｎｓ与ＴＧ、ＡｐｏＢ１００、ＬＰ（ａ）呈显著正相关，与ＨＤＬ－Ｃ、ＡｐｏＡＩ呈显著负相关。ＩＳＩ与ＴＧ、ＡｐｏＢ１００呈显著负相关，提示ＥＨ患者ＩＲ可能是影响脂代谢的重要因素之一。