Diabete & metabolisme最新文献

Diabetic and non-diabetic subjects with angina who underwent angiography and were subsequently treated surgically or medically and followed up for 5 years were analysed in order to assess coronary angiographic findings, efficacy of coronary artery bypass grafting and prognostic criteria in Type 2 diabetic patients with angina as compared to non-diabetic subjects. A total of 1853 of non-diabetic and 145 diabetic subjects underwent angiography, including respectively 857 and 68 who had surgery. Perioperative mortality, survival, reinfarction and asymptomaticity rates were measured. Multivariate analysis of risk factors and clinical features was performed. Diabetic patients had a higher frequency of multi-vessel stenoses (p < 0.001), a greater diffusion of stenoses (p < 0.005) and worse left ventricular motion (p < 0.005). No differences were found in perioperative infarction and mortality. Operated diabetic patients had a higher survival rate (p < 0.001) and a longer symptom-free period (p < 0.05) than unoperated diabetic patients. Operated diabetic patients had similar survival and more frequent recurrence of angina (p < 0.05) than operated non-diabetic patients. Survival rate was lower for unoperated diabetic patients than unoperated non-diabetic patients (p < 0.05). Recurrence of angina was similar. Multivariate analysis did not indicate diabetes as a factor affecting survival. It is concluded that surgery for Type 2 diabetic patients with coronary artery disease is a suitable therapeutic option conferring a reduction in mortality regardless of the presence of diabetes.

Although glucose is the major regulator of insulin secretion by pancreatic beta cells, its action is modulated by several neural and hormonal stimuli. In particular, hormones secreted by intestinal endocrine cells stimulate glucose-induced insulin secretion very potently after nutrient absorption. These hormones, called gluco-incretins or insulinotropic hormones, are major regulators of postprandial glucose homeostasis. The main gluco-incretins are GIP (gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like polypeptide-1). The secretion of GIP, a 42 amino acid polypeptide secreted by duodenal K cells, is triggered by fat and glucose. GIP stimulation of insulin secretion depends on the presence of specific beta-cell receptors and requires glucose at a concentration at least equal to or higher than the normoglycaemic level of approximately 5 mM. GIP accounts for about 50% of incretin activity, and the rest may be due to GLP-1 which is produced by proteolytic processing of the preproglucagon molecule in intestinal L cells. GLP-1 is the most potent gluco-incretin characterized so far. As with GIP, its stimulatory action requires a specific membrane receptor and normal or elevated glucose concentrations. Contrary to GIP, the incretin effect of GLP-1 is maintained in non-insulin-dependent diabetic patients. This peptide or agonists of its beta-cell receptor could provide new therapeutic tools for the treatment of Type II diabetic hyperglycaemia.

The files of 132 patients with Type 2 diabetes were retrospectively studied to characterize the influence of metabolic control and residual insulin secretion on neuropathy and retinopathy, the two most frequent degenerative diabetic complications. Patients were classified according to their metabolic control (mean HbA1C either < or > or = 8%; reference values: 3-6%) and residual endogenous insulin secretion (fasting plasma C-peptide levels either < or > or = 0.600 nmol/l). Neuropathy was more frequent in patients with poor metabolic control (32/64 = 50%) than in those adequately controlled (17/68 = 25%; p < 0.005). In both subgroups, the level of endogenous insulin secretion did not influence the prevalence of neuropathy. Retinopathy was less effected than neuropathy by the degree of metabolic control (37.5% in the subgroup with HbA1C > or = 8% v.s. 25% in the subgroup with HbA1C < 8%; p < 0.10), but was influenced by residual insulin secretion. Indeed, in patients with inadequate metabolic control, the prevalence of retinopathy was significantly increased in those with higher endogenous insulin secretion (51.4 versus 20.6%, p < 0.02) and thus probably higher insulin resistance. Furthermore, higher systolic arterial blood pressure was observed in the subgroups with a higher prevalence of retinopathy. Such conclusions were confirmed using multivariate analysis. Thus, in Type 2 diabetes, neuropathy is essentially affected by the degree of metabolic control, whereas retinopathy is also influenced by the level of residual endogenous insulin secretion and the presence of systolic hypertension.

Insulin secretory response to glucose changes with age. To elucidate age-dependent differences in pancreatic islet responsiveness to glucose, isolated islets from rats one week, three months and 14 months old were investigated in vitro. At three months of age, islet insulin secretion was increased five-fold by an acute glucose challenge. There was a significantly lower insulin response in both younger and older age groups. Islet insulin biosynthesis, as determined by the rate of incorporation of radioactive leucine into immunoprecipitable insulin, was lower at three months of age than at one week or 14 months. Insulin content was lowest in islets from the youngest rats and increased with age. The capacity for islet intracellular degradation of insulin was estimated according to the disappearance of tritiated leucine-labelled insulin during a 24-hour chase incubation. At a high glucose concentration, virtually no insulin was degraded intracellularly in islets from three-month-old rats, whereas islets from both younger and older animals showed a significant degradative capacity. High activities of a number of lysosomal enzymes in islets from one-week-old rats could account for the high degradative capacity and relatively low insulin content of these islets. Thus, low insulin response to glucose during early development may depend primarily on low insulin stores. However, during ageing, when islets are characterised by high insulin content, low response may depend primarily on impairment of beta-cell stimulus-secretion coupling, with high intracellular degradation of insulin resulting secondarily from an accumulation of insulin in the islets.

It is unclear whether reported histopathological changes in the endocrine pancreas of the GK rat (a spontaneous model of non-insulin-dependent diabetes) are related to the pathogenesis of hyperglycaemia or occur secondarily to metabolic alterations. We found that total pancreatic insulin stores in GK rats from the Paris colony were depleted by 62% (p < 0.01) in adult (4-month-old) overtly hyperglycaemic animals compared to those of normal Wistar control rats, and that beta-cell mass in GK pancreata was decreased to a similar extent (51%, p < 0.05). This indicates that decreased in vivo and in vitro insulin secretory response to glucose in GK rats could be due not only to impaired stimulus-secretion coupling for glucose in their beta cells but also to a reduced number of beta cells. Reduced total beta-cell mass in adult GK rats was associated with a noticeable alteration in the architecture of a subpopulation of islets: only large islets displayed signs of disorganization of the mantle-core relationship due to prominent fibrosis, with clusters of beta cells widely separated by strands of connective tissue. Our study also provides a first record of the pathophysiologic changes occurring in the GK rat from the neonatal period. Four-day-old GK pups demonstrated normal basal glycaemia compared to Wistar rats of the same age. GK islets displayed a well-preserved architecture, with normal staining of beta cells and no fibrosis. However, their total pancreatic insulin stores and total beta-cell mass were significantly lower [59% (p < 0.01) and 64% (p < 0.05) respectively] than those of controls. These data indicate that a reduction in islet tissue clearly predates the onset of diabetes (hyperglycaemia). Therefore, a reduction of total beta-cell mass should be considered as a primary feature in the pathological sequence leading to diabetes in GK rats, at least in those originating from the Paris colony.

Haemochromatosis is a common autosomal recessive disorder of iron metabolism caused by a gene in tight linkage with HLA class I genes. Despite intensive research, the molecular defect and underlying biochemical anomaly are still unknown. Diabetes, a serious complication of haemochromatosis, is frequently associated with cirrhosis which reduces life expectancy. Its development is related to iron excess, directly or through associated liver involvement, although the precise mechanisms of iron toxicity remain unclear. New concepts concerning its pathogenesis include insulin resistance and beta-cell dysfunction which are apparent well before insulin deficiency and can be reversed if iron depletion is promptly initiated. Today, earlier recognition of iron overload through active diagnostic approaches has a direct impact in reducing the frequency of diabetes among hemochromatosis patients. Presymptomatic diagnosis in the general population and among relatives of affected subjects currently relies on the detection of increased iron stores through medical awareness and family screening. Indirect gene diagnosis with serological and molecular markers of the HLA region can be provided for relatives of proven cases. As part of a genetic counselling process, this allows the identification of at-risk subjects before the onset of iron accumulation. Isolation of the gene and identification of the metabolic defect leading to increased iron absorption may have significant implications for future diagnostic procedures and preventive strategies in haemochromatosis.

The spontaneously diabetic BB rat is a well-established animal model of human insulin-dependent diabetes mellitus. Besides the lymphopenia gene (Iddm 1) and the MHC class-II genes of the RT1u haplotype (Iddm 2), at least one other non-MHC gene (Iddm 3) is considered essential for diabetes development. To investigate the participation of this third gene in the development of diabetes in our BB/OK rat subline, we analysed 119 [(BB/OK x DA)F1 x BB/OK] first backcross hybrids phenotypically and genotypically. Genotyping with 5 classical and 28 polymorphic microsatellite markers indicated that the third gene is located on chromosome 18, about 22 +/- 7 cM distal from the Olf locus (Iod score = 2.33). Significantly more diabetics than Iddm 1 and Iddm 2 homozygous nondiabetic subjects were homozygous for this locus. Interacting genes located on chromosomes X and/or 1 seem to be involved.