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N Kaiser

Publications and source records attributed to N Kaiser.

At least 37 records · Page 2Linked to original sources
PubMed2000

[Type 2 diabetes and beta cell apoptosis].

Type 2 diabetes mellitus features an asymptomatic insulin resistance phase preceding the onset of diabetes. Hyperglycemia occurs when a relative insulin deficiency appears, meaning that beta cell secretory dysfunction is a key element in type 2 diabetes pathophysiology. So far, insulin secretion deficiency is explained by pancreatic beta cell "exhaustion" phenomena. Recent data suggest that apoptotic mechanisms could explain insulin deficiency through a reduction in the absolute pancreatic beta cell number. Psammomys obesus (sand rat) is an animal model for type 2 diabetes mellitus, initially characterized by hyperinsulinism followed by insulin deficiency linked with a reduction in the number of pancreatic beta cells. Transition to diabetes can be observed following changes in usual lifestyle of the sand rat. In the desert, caloric intake is low and physical expenditure is heavy. In the laboratory, animals turn diabetic as early as 4 days following a high calorie diet. At a later stage, diabetes is irreversible and animals die from diabetic ketoacidosis. beta cell apoptosis rate is low in non diabetic animals and increases 14-fold by 20 days after diabetes onset. At this stage, cells undergoing apoptosis can be observed, coexisting with necrotic cells without any insulitis. Similar results were obtained in vitro in isolated pancreatic islets that were exposed to increasing glucose concentrations, suggesting that chronic hyperglycemia plays a role in the onset or the deterioration of the process. However, precise mechanisms of apoptosis in this case remain poorly understood. Aminoguanidin does not prevent beta cell apoptosis in vitro, suggesting that advanced glycation products or NO production are not involved in this beta cell destruction process. Similar mechanisms secondary to hyperglycemia could play a role in the diabetes process in man and explain the marked insulin secretory deficiency that is sometimes observed in these patients. In addition to its preventing role on diabetes complication, the obtention of normoglycemia could help maintaining beta cell function.

Animals↗
PubMed1999

Interaction between genetic and dietary factors determines beta-cell function in Psammomys obesus, an animal model of type 2 diabetes.

The gerbil Psammomys obesus develops nutrition-dependent diabetes. We studied the interaction between diet and diabetic predisposition for beta-cell function. A 4-day high-energy (HE) diet induced a 3-, 4-, and 1.5-fold increase in serum glucose, insulin, and triglycerides, respectively, in diabetes-prone (DP) but not diabetes-resistant (DR) P. obesus. Hyperglycemia and concurrent 90% depletion of islet immunoreactive insulin stores were partially corrected by an 18-h fast. In vitro early insulin response to glucose was blunted in both DR and DP perifused islets. The HE diet augmented early and late insulin response in DR islets, whereas in DP islets, secretion progressively declined. Dose-response studies showed a species-related increase in islet glucose sensitivity, further augmented in DP P. obesus by a HE diet, concomitant with a decreased threshold for glucose and a 55% reduction in maximal response. These changes were associated with a fourfold increase in glucose phosphorylation capacity in DP islets. There were no differences in islet glucokinase (GK) and hexokinase (HK) Km; however, GK Vmax was 3.7- to 4.6-fold higher in DP islets, and HK Vmax was augmented 3.7-fold by the HE diet in DP islets. We conclude that the insulin-resistant P. obesus has an inherent deficiency in insulin release. In the genetically predisposed P. obesus (DP), augmented islet glucose phosphorylation ability and diet-induced reduction of the glucose threshold for secretion may lead to inadequate insulin secretion and depletion of insulin stores in the presence of caloric abundance. Thus, genetic predisposition and beta-cell maladaptation to nutritional load seem to determine together the progression to overt diabetes in this species. It is hypothesized that similar events may occur in obese type 2 diabetic patients.

Animal Nutritional Physiological Phenomena↗
PubMed1999

Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes.

The gerbil Psammomys obesus develops nutrition-dependent diabetes associated with moderate obesity. The disease is characterized by initial hyperinsulinemia, progressing to hypoinsulinemia associated with depleted pancreatic insulin stores. The contribution of changes in beta-cell turnover to insulin deficiency was investigated in vivo during transition to overt diabetes. Normo glycemic diabetes-prone P. obesus animals who were given a high-calorie diet developed hyperglycemia within 4 days, which was found to be associated with a progressive decline in pancreatic insulin content. This was accompanied by a transient increase in beta-cell proliferative activity and by a prolonged increase in the rate of beta-cell death, culminating in disruption of islet architecture. The hypothesis that "glucotoxicity" was responsible for these in vivo changes was investigated in vitro in primary islet cultures. Exposure of islets from diabetes-prone P. obesus to high glucose levels resulted in a dose-dependent increase in beta-cell DNA fragmentation. In contrast, high glucose levels did not induce DNA fragmentation in rat islets, whereas islets from a diabetes-resistant P. obesus line exhibited a reduced and delayed response. Aminoguanidine did not prevent glucose-induced beta-cell DNA fragmentation in vitro, suggesting that formation of nitric oxide and/or advanced glycation end products plays no major role. Elevated glucose concentrations stimulated beta-cell proliferation in both rat and P. obesus islets. However, unlike the marked long-lasting effect in rat islets, only a transient and reduced proliferative response was observed in P. obesus islets; furthermore, beta-cell proliferation was inhibited after prolonged exposure to elevated glucose levels. These results suggest that hyperglycemia-induced beta-cell death coupled with reduced proliferative capacity may contribute to the insulin deficiency and deterioration of glucose homeostasis in P. obesus. Similar adverse effects of hyperglycemia could play a role in the evolution of type 2 diabetes in genetically susceptible individuals.

Animals↗
PubMed1999

Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose.

In type 2 diabetes, chronic hyperglycemia has been suggested to be detrimental to beta-cell function, causing reduced glucose-stimulated insulin secretion and disproportionately elevated proinsulin. In the present study, we investigated the effect on several beta-cell functions of prolonged in vitro exposure of human pancreatic islet cultures to high glucose concentrations. Islets exposed to high glucose levels (33 mmol/l) for 4 and 9 days showed dramatic decreases in glucose-induced insulin release and in islet insulin content, with increased proportion of proinsulin-like peptides relative to insulin. The depletion in insulin stores correlated with the reduction in insulin mRNA levels and human insulin promoter transcriptional activity. We also demonstrated that high glucose dramatically lowered the binding activity of pancreatic duodenal homeobox 1 (the glucose-sensitive transcription factor), whereas the transcription factor rat insulin promoter element 3b1 activator was less influenced and insulin enhancer factor 1 remained unaffected. Most of these beta-cell impairments were partially reversible when islets first incubated for 6 days in high glucose were transferred to normal glucose (5.5 mmol/l) concentrations for 3 days. We conclude that cultured human islets are sensitive to the deleterious effect of high glucose concentrations at multiple functional levels, and that such mechanisms may play an important role in the decreased insulin production and secretion of type 2 diabetic patients.

Adult↗
PubMed1997

Substrate autoregulation of glucose transport: hexose 6-phosphate mediates the cellular distribution of glucose transporters.

Exposure of rat skeletal muscle and skeletal muscle cell lines to high glucose levels results in a time- and dose-dependent reduction of the rate of hexose uptake, paralleled by a reduction in the plasma membrane density of glucose transporters. The mechanism of this process was investigated in cultured L8 myocytes. Low concentrations (0.5-2.0 mmol/l) of deoxyglucose mimicked the downregulatory action of 20 mmol/l glucose both regarding the time-course and magnitude of the effect, but in an irreversible manner. A dose-dependent relationship between intracellular accumulation of deoxyglucose 6-phosphate and the magnitude of the downregulatory response was observed. Depletion of intracellular deoxyglucose 6-phosphate restored the rate of hexose transport to the control level. The reduction of hexose transport activity by deoxyglucose occurred independently of ATP depletion which by itself produced the opposite effect. The effects of deoxyglucose and high glucose on hexose transport were associated with reduced transport maximal velocity and GLUT1 transporter abundance in the plasma membranes of myocytes, as assessed by cell surface biotinylation. The reduction of myocyte GLUT1 mRNA content, observed after exposure to high glucose, did not accompany the transport down regulatory action of deoxyglucose. We suggest that hexose 6-phosphate is the mediator of the downregulatory signal for subcellular redistribution of GLUT1 in L8 myocytes. The signal responsible for reducing the GLUT1 mRNA level may be related to glucose metabolites downstream of the hexokinase reaction.

Adenosine Triphosphate↗
PubMed1997

Characterization of the unusual insulin of Psammomys obesus, a rodent with nutrition-induced NIDDM-like syndrome.

Psammomys obesus fed a high-calorie diet develops a NIDDM-like syndrome. The use of reverse-phase high-performance liquid chromatography (HPLC) to study Psammomys insulin biosynthesis and release revealed a very delayed elution time for the Psammomys insulin peak appearing near the position of human proinsulin. This unusual peak was initially thought to represent partially processed insulin on the basis of its molecular size and susceptibility to trimming by carboxypeptidase B (CpB). However, the findings of an active carboxypeptidase E (CpE) enzyme and the normal amidated forms of gastrin and cholecystokinin octapeptide (CCK-8) in Psammomys tissues were inconsistent with CpE-related aberrant processing of insulin. Moreover, amino acid sequencing of the delayed peak of Psammomys insulin revealed fully processed insulin with amino acid sequence as predicted by the cDNA. The unique presence of a B-30 phenylalanine residue, resulting in an increased hydrophobicity of the insulin molecule, probably underlies the marked delay in elution time on HPLC. The unusual structure of Psammomys insulin does not appear to contribute to the proinsulinemia observed in diabetic Psammomys since the HPLC-purified molecule did not inhibit PC1 and PC2 convertase activities in an in vitro assay.

Amino Acid Sequence↗
PubMed1997

From sand rats to diabetic patients: is non-insulin-dependent diabetes mellitus a disease of the beta cell?

It has been debated for the past two decades whether non-insulin-dependent diabetes mellitus (NIDDM) is caused by insulin deficiency or insulin resistance. In this review we summarise the data which unequivocally indicate that insulin response to glucose is grossly deficient in patients with impaired glucose tolerance and NIDDM. Furthermore, we review the findings for Psammomys obesus (the sand rat), an animal with spontaneous obesity, insulin resistance and diabetes which has been used as the prototype for "hyperinsulinaemic NIDDM". A large proportion of circulating insulin in this animal consists of proinsulin and its split products, apparently resulting from hyperglycaemia-driven overstimulation of the beta cell, with depletion of its insulin stores. In vitro studies demonstrate that this "glucose toxic" effect can be reproduced in Psammomys islets but not in those of normal rats. This would indicate that increased demand for insulin production leads to aberrations in proinsulin production and processing only in beta cells with inherent (genetic?) defects. We also point to clinical findings which cast doubt on the practical importance of insulin resistance for the glucose homeostasis of NIDDM patients. In these cases, moderate doses of insulin administered by insulin pumps can induce near-normoglycaemia in NIDDM.

Animals↗
PubMed1996

Regulation by metformin of the hexose transport system in vascular endothelial and smooth muscle cells.

1. The effect of the biguanide metformin on hexose transport activity was studied in bovine cultured aortic endothelial (BEC) and smooth muscle cells (BSMC). 2. Metformin elevated the rate of hexose transport determined with 2-deoxyglucose (2DG) in a dose- and time-dependent manner in both cell types. Similar ED50 values (0.8-1.0 mM) were determined for the effect of metformin on 2DG uptake in both BEC and BSMC following 24 h exposure to increasing concentrations of metformin, with maximal stimulation at 2 mM. 3. In BEC, metformin increased the hexose transport rate 2-3 fold at all glucose concentrations tested (3.3-22.2 mM). In BSMC incubated with 22.2 mM glucose, metformin elevated the hexose transport approximately 2 fold. The drug was also effective at lower glucose levels, but did not exceed the maximal transport rate observed in glucose-deprived cells. 4. Similar results were obtained when the effect of metformin on hexose transport activity was assessed with the non-metabolizable hexose analogue, 3-O-methylglucose, suggesting that the drug affects primarily the rate of hexose transport rather than its subsequent phosphorylation. 5. The metformin-induced increase in hexose transport in BSMC treated for 24 h with the drug correlated with increased abundance of GLUT1 protein in the plasma membrane, as determined by Western blot analysis. 6. These data indicate that in addition to its known effects on hexose metabolism in insulin responsive tissues, metformin also affects the hexose transport system in vascular cells. This may contribute to its blood glucose lowering capacity in patients with Type 2, non-insulin-dependent diabetes mellitus.

Animals↗
PubMed1996

Increased susceptibility of islets from diabetes-prone Psammomys obesus to the deleterious effects of chronic glucose exposure.

Patients with noninsulin-dependent diabetes (NIDDM) show an increase in the relative plasma levels of proinsulin and proinsulin conversion intermediates, which is corrected by strict glycemic control. This observation suggests that hyperglycemia per se may be responsible for generating the aberrant plasma hormone profile. The question remains, however, whether a genetic predisposition to NIDDM underlies the failure of the insulin production machinery to meet a prolonged increase in secretory demand. In this study, islet monolayer cultures from the diabetes-prone Psammomys obesus and normal diabetes-resistant rats were exposed to RPMI 1640 medium containing either 11.1 or 33.3 mM glucose; insulin-related peptides were resolved by HPLC. Prolonged exposure (10 days) of rat islets to high glucose resulted in a reduced a secretory response to an acute glucose stimulus associated with a 37% reduction in the insulin content but no change in the proinsulin/insulin ratio. When subjected to a similar protocol, islets from prediabetic Psammomys lost the insulin response to glucose; beta-cell insulin content was reduced by about 70%, and the proportion of proinsulin-related peptides increased from 18% to 38%. In the in vivo situation, pancreatic extracts from nonfasted diabetic Psammomys contained 36% proinsulin-related peptides in contrast to 15% in pancreatic extracts from nondiabetic animals. Thus, prolonged in vitro exposure of prediabetic Psammomys islets to high levels of glucose could reproduce the modified beta-cell secretory profiles observed in vivo in the diabetic animal. These results support the hypothesis that hyperproinsulinemia in NIDDM is secondary to the inability of beta-cells to meet a sustained increase in insulin demand, whereas individuals with normal beta-cells may meet such demand with an adequate output of mature insulin.

Animals↗
PubMed1995

Insulin secretion in obese and non-obese NIDDM.

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.

Animals↗
PubMed1995

Recombinant mapping of the familial hyperinsulinism gene to an 0.8 cM region on chromosome 11p15.1 and demonstration of a founder effect in Ashkenazi Jews.

A gene for autosomal recessive familial hyperinsulinism (HI) (OMIM: 256450), a neonatal metabolic disease characterized by inappropriate insulin secretion in the presence of severe hypoglycemia, was recently mapped to a 6.6 cM interval between the markers D11S926 and D11S928 on chromosome 11p in 15 families (1). In the current study we evaluated six additional families and five new markers, and further localized the gene between D11S419 and D11S1310. Using genotype data from CEPH Version 7 and data generated from this study, this region was estimated to be 0.8 cM in length. Significant linkage disequilibrium between markers and the HI gene was observed over a region of 10.3 cM (11 pter-D11S926-D11S1308-11pcen) for Ashkenazi Jewish chromosomes. Haplotype analysis showed that 12 of 36 HI chromosomes, versus one of 36 non-HI chromosomes, bore a specific haplotype for D11S419-D11S902-D11S921 (p < 0.0007), strongly suggesting a founder effect in this ethnic group.

Alleles↗
PubMed1995

Hyperproinsulinemia in the diabetic Psammomys obesus is a result of increased secretory demand on the beta-cell.

We have recently shown that the diabetic syndrome in Psammomys obesus is characterized by severe depletion of islet immunoreactive insulin (IRI) stores together with a marked increase in the islet proinsulin to insulin ratio. In the present in vitro studies, we show marked enhancement of proinsulin biosynthesis in islets from diabetic P. obesus (approximately 8-fold compared to nondiabetic islets). Proinsulin to insulin conversion and insulin degradation do not differ significantly between diabetic and nondiabetic islets. The rate of IRI secretion at a stimulatory concentration of glucose (16.7 mM) is comparable in diabetic and nondiabetic animals, but at a nonstimulatory glucose concentration (0 mM), islets obtained from diabetic animals show significant IRI release. beta-Cells from diabetic P. obesus also exhibited increased secretion of newly synthesized proinsulin and conversion intermediates under stimulatory conditions. Moreover, a novel secretory compartment, highly enriched in newly synthesized C peptide, characterized the beta-cells of diabetic animals. Our data suggest that the marked insulin depletion observed in diabetic islets is probably due to a hyperglycemia-driven increase in secretory demand that is not met by the enhanced biosynthetic capacity of these islets. This leads to relative enrichment of the depleted diabetic islets with immature secretory granules of a higher proinsulin content.

Animals↗