Cerasi E, Nesher R, Gadot M, Gross D, Kaiser N
Department of Endocrinology and Metabolism, Hadassah University Hospital, Jerusalem, Israel.
Diabetes Res Clin Pract. 1995 Aug;28 Suppl:S27-37. doi: 10.1016/0168-8227(95)01083-p.
Both the insulin response to glucose and the sensitivity to insulin show large variation in the normal population. Many subjects have either a markedly low insulin response or low sensitivity to insulin, with nevertheless normal glucose tolerance. For such subjects to become diabetic, insulin secretion or insulin action must further deteriorate with time, or other factors are added which tip the balance towards diabetes. Most evidence to date indicates that reduced beta-cell responsiveness and reduced insulin sensitivity co-exist in subjects prior to developing NIDDM. Both insulin secretion and insulin action are genetically controlled and influenced by intrauterine and neonatal factors. Insulin secretion and insulin action vary inversely in a closely linked manner; inability to fully compensate for changes in one variable may generate a functional deficit in glucose homeostasis. Subjects combining low functions would run a proportionately larger risk of decompensating the glucose tolerance and be more vulnerable, in terms of diabetes susceptibility, to factors that further reduce insulin output or insulin action. Careful analysis of existing data prompts us to ascribe a dominating role to the impairment of insulin secretion in the pathogenesis of IGT and NIDDM. Patients with NIDDM also exhibit increased proportions of proinsulin and proinsulin conversion intermediates. We used hyperinsulinaemic diabetic and non-diabetic Psammomys obesus to study the possible relationship between steady-state pancreatic insulin stores and the proportion of proinsulin-related peptides in the plasma and the pancreas. A marked increase in these peptides was associated with 90% reduction in insulin stores of the pancreas. After food deprivation, the depletion of pancreatic insulin in the diabetic animals was partially corrected, and the proinsulin/insulin ratio normalized. In contrast, non-diabetic psammomys showed only 50% reduction in pancreatic insulin stores under non-fasting conditions, with no change in proinsulin/insulin ratio. These findings suggest that in the diabetic Psammomys obesus, pancreatic capacity for storage/production of insulin is limited; the metabolic consequences of this limitation are amplified by increased secretory demand secondary to insulin resistance, thus facilitating the establishment of hyperglycaemia, which may in itself further exacerbate the pancreatic dysfunction.
在正常人群中，胰岛素对葡萄糖的反应以及对胰岛素的敏感性都存在很大差异。许多受试者要么胰岛素反应明显较低，要么对胰岛素的敏感性较低，但糖耐量仍正常。对于这些受试者来说，要发展为糖尿病，胰岛素分泌或胰岛素作用必须随时间进一步恶化，或者加入其他使平衡向糖尿病倾斜的因素。迄今为止的大多数证据表明，在发展为非胰岛素依赖型糖尿病（NIDDM）之前，受试者同时存在β细胞反应性降低和胰岛素敏感性降低的情况。胰岛素分泌和胰岛素作用均受遗传控制，并受子宫内和新生儿因素的影响。胰岛素分泌和胰岛素作用以密切相关的方式呈反向变化；无法完全补偿一个变量的变化可能会导致葡萄糖稳态出现功能缺陷。功能低下的受试者失去糖耐量的风险会相应增加，并且就糖尿病易感性而言，对进一步降低胰岛素分泌或胰岛素作用的因素更敏感。对现有数据的仔细分析促使我们将胰岛素分泌受损在糖耐量受损（IGT）和NIDDM发病机制中的主导作用归因于此。NIDDM患者还表现出胰岛素原和胰岛素原转化中间产物的比例增加。我们使用高胰岛素血症的糖尿病和非糖尿病肥胖沙鼠来研究稳态胰腺胰岛素储备与血浆和胰腺中胰岛素原相关肽比例之间的可能关系。这些肽的显著增加与胰腺胰岛素储备减少90%相关。禁食后，糖尿病动物胰腺胰岛素的消耗得到部分纠正，胰岛素原/胰岛素比值恢复正常。相比之下，非糖尿病肥胖沙鼠在非禁食条件下胰腺胰岛素储备仅减少50%，胰岛素原/胰岛素比值无变化。这些发现表明，在糖尿病肥胖沙鼠中，胰腺储存/产生胰岛素的能力有限；这种限制的代谢后果因胰岛素抵抗继发的分泌需求增加而放大，从而促进高血糖症的形成，而高血糖症本身可能会进一步加剧胰腺功能障碍。
