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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The author summarizes mechanisms by which insulin resistance and compensatory hyperinsulinism are manifested in the clinical picture. He divides the mechanisms into prereceptor, receptor and postreceptor mechanisms. The latter dominate in the population quantitatively and thus also by their impact because they create the so-called 5H syndrome (association of hyperinsulinism with hyperglycaemia (NIDDM), hyperlipoproteinaemia, hypertension, hirsutism and the polycystic ovary syndrome) or the so-called hormonal metabolic syndrome X, lethal tetrad, metabolic syndrome, syndrome of insulin resistance). The term syndrome X does not appear suitable as it is frequently mistaken for coronary X syndrome which probably is also conditioned by hyperinsulinism, for the hormonal metabolic X syndrome and probably also fot the "fragile X syndrome" in genetics. The 5H syndrome is caused by a postreceptor disorder of insulin efficiency for which so far the molecular basis and dominating organ site have not yet been defined adequately. Hyperinsulinism is conceived as an insulin resistance compensating phenomenon. In its development participates, however, in addition to compensatory hypersecretion also impaired insulin utilization (liver, muscles) and an impaired primary secretory response caused probably by a disorder of blood sugar control (glucokinase, GLUT 2). This is suggested by the frequently inadequate response of the blood sugar level, IRI and C-peptide during the oral glucose tolerance test (OGGT). A hyperinsulinaemic response may be encountered when the blood sugar curve is normal, flat, in impaired glucose tolerance and in diabetes. Thus OGGT alone is not suited for the early detection of the 5H syndrome unless concurrently the IRI and C-peptide response is recorded.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Clinical manifestations of the insulin resistance syndrome. The hormonal-metabolic syndrome X, the 5H syndrome and their etiopathogenesis]. 772 46

The results of many cross-sectional studies have indicated that insulin resistance is a consistent, abnormal metabolic characteristic of people with NIDDM. Recently many investigators studying different populations have reported that insulin resistance is a prediabetic abnormality and is a major risk factor for the disease. Although deficient insulin secretion is also characteristic of people with NIDDM, there are no data to indicate that it precedes the onset of the disease, except in rare instances of families with glucokinase mutations. Therefore, in most cases, it appears that deficient insulin secretion occurs secondarily to insulin resistance, and there is experimental evidence indicating the mechanism of this effect. The clearest examples of this pathophysiologic mechanism are persons with insulin receptor mutations and severe insulin resistance in whom NIDDM develops despite normal insulin secretion. In addition, prospective studies have indicated that NIDDM rarely develops in the most insulin-sensitive subjects, and the relatively lower insulin concentrations in patients with a known beta-cell defect--that is a glucokinase mutation--are compatible with normal glucose tolerance if ideal whole body insulin sensitivity is maintained. These data indicate beyond a reasonable doubt that insulin resistance is a sufficient cause of NIDDM and in most instances is necessary for its development.
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PMID:Agonist: the case for insulin resistance as a necessary and sufficient cause of type II diabetes mellitus. 773 20

NIDDM is likely to have a major genetic component in view of the different prevalence between ethnic groups, the familial clustering, and the high concordance in monozygotic twins. Linkage analysis of extended pedigrees of patients with maturity-onset diabetes of the young (MODY) identified the glucokinase gene mutations. Specific phenotypes have also led to the discovery of the insulin gene mutations in patients with high insulin or proinsulin levels, to the insulin receptor mutations in patients with marked insulin resistance, and to the mutations in mitochondrial DNA associated with deafness and maternal inheritance. These four types of diabetogenic gene mutations account for only a minor proportion of NIDDM. Direct screening for mutations in candidate genes with single-strand conformation polymorphism or heteroduplex screening or with direct sequencing in the diabetic patients with the appropriate pathophysiological abnormality can be a successful strategy. Genetic diagnosis provides clear definite diagnosis and specific therapies, such as IGF-1 for the insulin receptor mutations and coenzyme Q10 for the mitochondrial gene mutations.
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PMID:[Genetic diagnosis of diabetes mellitus]. 778 64

Maturity-onset diabetes of the young (MODY) is a subtype of non-insulin dependent diabetes mellitus, with early age of onset. MODY is genetically heterogeneous, associated with glucokinase mutations and a locus on chromosome 20q; in about 50% of cases, its genetic background is unknown. We have studied 12 families in which MODY is unlinked to either glucokinase or chromosome 20q markers, and find significant evidence for linkage with microsatellite markers on chromosome 12q, most likely within a 7 centimogran interval bracketed by D12S86 and D12S342. The disease was estimated to be linked to this chromosome region in approximately 50% of families in a heterogeneity analysis. These MODY patients exhibit major hyperglycaemia with a severe insulin secretory defect, suggesting that the causal gene is implicated in pancreatic beta-cell function.
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PMID:A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. 779 49

Candidate genes for NIDDM have been screened in Japanese. Mutations in the glucokinase gene were found in apparent late-onset NIDDM patients as well as in MODY patients. Clinical characteristics in the subjects with glucokinase gene mutations are similar to those in Caucasian subjects; diabetes mellitus is generally mild and some patients actually remain as having impaired glucose tolerance. Of great interest is that all affected subjects show blunted insulin secretion response to the glucose challenge, which is most commonly observed in Japanese NIDDM patients. Thus, it is possible that impairment in the regulation of glucokinase gene expression or its enzyme activity is associated with at least some Japanese NIDDM patients, though the prevalence of the mutations in the coding region is relatively low. In contrast, a mitochondrial tRNA(Leu(UUR)) gene mutation at np 3243 appears to be much more common, and diabetes due to this mutation has a progressive nature. Insulin secretory capacity progressively decreases, eventually reaching an insulin-dependent state in most patients. A surprising result is that this gene mutation is often observed in ICA-positive IDDM patients who were initially non-insulin-dependent, so called slowly progressive IDDM patients. These results suggest that the mitochondrial gene mutation may cause beta cell loss in addition to defects in glucose-induced signaling in pancreatic beta cells, which explains that the mitochondrial gene mutation manifests a wide range of diabetic phenotypes, from NIDDM to IDDM.
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PMID:NIDDM--genetic marker; glucose transporter, glucokinase, and mitochondria gene. 785 92

We have applied the technique of single-strand conformation polymorphism analysis to detect mutations of the glucokinase gene in 50 Japanese patients with late-onset type 2 diabetes and in 50 normal Japanese subjects. Out of the 50 patients with late-onset type 2 diabetes, we observed three kinds of variant patterns: one in exon 1b, one in exon 4, and one in exon 5. The incidence of these patterns was one in exon 1b, two in exon 4 and one in exon 5. Direct sequencing of exon 1b and exon 5 revealed mutations in intron areas at the 12th nucleotide downstream from the 5' splice points in two cases. Direct sequencing of exon 4 revealed a heterozygous silent mutation, CCC[Pro]-->CCG[Pro] at codon 145. In contrast, 50 normal Japanese subjects showed no variant patterns in any exons. Our results showed that although 8% (4 out of 50) of Japanese patients with late-onset type 2 diabetes have variant forms of the glucokinase gene, none is expected to cause apparent qualitative changes in glucokinase. We think that the frequency of mutations of the glucokinase gene which could cause qualitative change is very low in Japanese patients with late-onset type 2 diabetes.
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PMID:Variant forms of glucokinase gene in Japanese patients with late-onset type 2 diabetes. 788 97

Several lines of evidence suggest a strong genetic component to NIDDM. To clarify the role of glucokinase gene in the development of NIDDM, restriction fragment length polymorphism (RFLP) of glucokinase gene and 3' microsatellite polymorphism analyses by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) were performed in NIDDM and control subjects. Compared to NIDDM with 1.3 kb allele/Pvu I digestion of glucokinase, 10% of NIDDM did not demonstrate 1.3 kb allele and these patients were characterized by increased insulin secretion. In 3' microsatellite polymorphism analysis, autoradiography of PCR products revealed three different alleles, including Z, Z + 2 and Z + 4. Z was the most common allele in both NIDDM and nondiabetic controls. There was no significant allele associated with NIDDM. Frequency of the homozygote Z/Z genotype was significantly lower in NIDDM subjects (16.7%) compared to normal control (46.7%)(p < 0.05). There was no difference in clinical findings according to 3' microsatellite genotypes in NIDDM. These data suggest that there does not appear to be a significant glucokinase allele associated with NIDDM but Z/Z genotype may play a suppressive role in the pathogenesis of a certain type of NIDDM in Korea. Further studies may be required to identify the molecular basis of this association.
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PMID:Polymorphism of glucokinase gene in non-insulin dependent diabetes mellitus. 791 22

Non-insulin-dependent diabetes (NIDDM) is a heterogeneous state involving various degrees of beta-cell dysfunction and insulin resistance, although the relative importance of these two factors is controversial. Several single gene disorders of carbohydrate metabolism have their main pathophysiological defect largely restricted to the beta-cell or to insulin-sensitive tissues. We have noted that with insulin resistance the fasting plasma glucose is often normal and severe hyperglycaemia occurs after a glucose load. By contrast, in glucokinase-deficient diabetes, which is characterised by reduced insulin secretion, the reverse is the case. Supportive evidence showing that beta-cell dysfunction and insulin resistance may have different effects on fasting and post-prandial glucose concentrations comes from studies of identical twins of NIDDM patients, hemi-pancreatectomised normal subjects, and insulin-resistant Asian subjects. NIDDM is usually preceded by a period of less severe hyperglycemia, referred to as impaired glucose tolerance (IGT). Studies of the IGT phase usually conclude that insulin resistance is the major abnormality and is thus the primary defect in NIDDM. However, the definition of IGT is based on the 2 h plasma glucose after an oral glucose-tolerance test without consideration of the fasting glucose concentrations (provided these concentrations are non-diabetic). Our observations suggest that this definition of IGT may result in the over-representation of insulin-resistant individuals and the under-representation of subjects with beta-cell dysfunction in any cross sectional study of IGT. The belief that the prediabetic state of IGT is dominated by insulin resistance may be a self-fulfilling prophesy because of the excessive emphasis put on the post-prandial rather than the fasting state.
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PMID:Insulin resistance as the major cause of impaired glucose tolerance: a self-fulfilling prophesy? 799 82

To investigate the possible contribution of glucokinase (GCK) and adenosine deaminase (ADA) loci to the genetic susceptibility to type 2 (non-insulin-dependent) diabetes mellitus, we studied the association of these loci with type 2 diabetes in the Japanese population. Fifty patients with type 2 diabetes and 50 control subjects were analyzed for microsatellite polymorphism 3' to the GCK gene and PstI polymorphism in the ADA gene by polymerase chain reaction. The frequency of the most common GCK allele (Z) was significantly lower in type 2 diabetic patients than that in control subjects and a longer Z + 2 allele was more common in type 2 diabetic patients (26% vs. 15%, P = 0.053), particularly in those with younger age of onset (33% vs. 15%, younger onset type 2 diabetes vs. control, P = 0.014). The frequency of genotypes containing at least one Z + 2 allele was significantly more common in type 2 diabetic patients (46% vs. 28%, P < 0.05), particularly in those with younger age of onset (61% vs. 28%, relative risk 4.00, P < 0.01). In contrast, there was no difference in allelic or genotypic frequencies of PstI polymorphism in the ADA gene between the two groups. Despite the association between the GCK locus and type 2 diabetes, none of the patients had known mutations (Glu265-->AM265, Glu279-->AM279, Gly299-->Arg299, Glu300-->Gln300, Leu309-->Pro309). These results suggest that the GCK locus, but not the ADA locus, contributes to the genetic susceptibility to type 2 diabetes in Japanese.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early-onset type 2 (non-insulin-dependent) diabetes mellitus is associated with glucokinase locus, but not with adenosine deaminase locus, in the Japanese population. 792 73

Glucokinase is a key enzyme of glucose metabolism that phosphorylates glucose to glucose-6-phosphate (G-6-P). This is the first step of glucose metabolism after the uptake of glucose by glucose transporter 2 (GLUT 2). Glucokinase is one of the hexo-kinases and is expressed only in pancreatic beta cells and hepatocytes. Recently it was reported that glucokinase gene is associated with some families with MODY (maturity-onset diabetes of the young). As MODY is a subtype of diabetes which is inherited autosomal dominantly, the correlation of diabetes with glucokinase gene was vigorously studied in many laboratories. The first mutation in exon 7 of the glucokinase gene was reported in 1992. Since the first report of the glucokinase gene mutation in exon 7, a number of mutations and a deletion were reported to be associated with MODY or late-onset NIDDM. But investigations by many groups revealed that glucokinase gene abnormalities are responsible for less than one per cent of NIDDM which is relatively small compared with diabetes with mitochondrial gene alterations.
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PMID:[Glucokinase gene abnormalities in maturity-onset diabetes of the young (MODY) and late-onset NIDDM]. 798 82


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