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

Diabetes mellitus is a clinically heterogeneous disorder which is characterized by hyperglycaemia due to an absolute or relative deficiency of insulin. Both genetic and non-genetic factors contribute to its development and, as such, it represents a multifactorial disorder. In addition, it may also be, in some instances, a polygenic disorder resulting from the cumulative effects of several genes with or without environmental factors. Serological and/or DNA markers for genes that confer susceptibility to the insulin-dependent form of the disorder (IDDM; type 1) have been identified in the HLA-D region of chromosome 6 and near the insulin gene on chromosome 11. Patients with non-insulin-dependent diabetes mellitus (NIDDM; type 2) make up a more heterogeneous group than those with IDDM and it is likely that in these patients similar clinical phenotypes may be produced by different genetic defects. The synthesis of either an abnormal insulin/proinsulin molecule or an abnormal insulin receptor can confer susceptibility to NIDDM. The genes encoding insulin and the insulin receptor are on chromosomes 11 and 19, respectively. In addition, studies of restriction fragment length polymorphism and disease associations suggest that two other genes may contribute to the development of NIDDM on chromosome 11, one near the insulin gene on the short arm of this chromosome and the other near the apolipoprotein A-I gene on the long arm. None of the susceptibility genes that have been identified to date causes diabetes in the absence of other genetic or non-genetic contributing factors, which is consistent with a multifactorial or polygenic origin for this disorder.
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PMID:The molecular genetics of diabetes mellitus. 289 28

The standard treatment of NIDDM consists of diet, oral hypoglycaemic agents and, mostly as a last resort, insulin. Indications for insulin therapy cannot be generalized for the whole population of NIDDM patients. The defined objectives of therapy for the individual patient will determine the choice and intensity of therapy. These will usually be either a relief of hyperglycaemic symptoms in the elderly patient or normoglycaemia, as in the insulin-dependent diabetic patients, in order to prevent acute and chronic complications. Primary insulin treatment is advisable in patients with hyperglycaemic symptoms and fasting blood glucose levels above 15 mmol/l, as in these patients the major defect will be insulin deficiency rather than insulin resistance. The correction of long lasting hyperglycaemia partly restores insulin sensitivity and B cell function, thereby allowing sequential reduction of insulin dosage. When metabolic control can be sustained with low insulin dosages some of these patients may later respond well to oral hypoglycaemic agents or to diet alone. In the management of non-insulin-dependent diabetic patients it is of great importance to recognize in time when treatment with oral hypoglycaemic agents fails. Insulin therapy should not be withheld on the presumption that it will cause weight gain and will promote development of macrovascular disease. Weight gain can be reduced by adequate dietary counselling and the level of macrovascular risk factors reduces with improved metabolic control. In this context also it should be realized that the correction of hypertension, hyperlipidaemia and the cessation of cigarette smoking is probably of equal importance. Insulin therapy regimens which have been used in non-insulin-dependent diabetic patients have been the same as prescribed for insulin dependent patients. When considering the fact that hepatic overproduction of glucose is the major determinant of fasting blood glucose level and that postprandial glycaemic excursions are superimposed on this level it seems reasonable to aim for normalization of the basal hepatic glucose production. A bedtime injection of an intermediate or long acting insulin can be used for this aim. Other therapeutical approaches which have been studied recently are the use of combinations of insulin and oral hypoglycaemic agents and the use of proinsulin as an alternative for intermediate acting insulin. Before these forms of therapy can be advocated long-term clinical studies are necessary to define their therapeutic role.
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PMID:Insulin treatment of non-insulin-dependent diabetes mellitus. 307 3

In Type II, non-insulin-dependent diabetes, insulin secretion is often reduced to the point where oral hypoglycaemic agents fail to control the plasma glucose level. We studied 12 patients (age 41-66 years; 4 lean, 8 obese) with Type II diabetes mellitus for 1-25 years who were uncontrolled despite maximal dose glibenclamide and metformin. After withdrawal of medication, blood glucose control was determined by measuring glucose before and 2 h after each meal for 48 h, and beta-cell function by insulin or C-peptide response to glucagon and to iv glucose. Following these tests, intensive insulin treatment (CSII) was initiated, and near-euglycaemia (mean of 7 daily glucose determinations less than 7.7 mmol/l) was maintained for 16.6 +/- 1.5 days, at which time the tests were repeated. Mean daily insulin requirement was 61 +/- 9 IU (0.81 +/- 0.09 IU/kg). Glucose control was improved after cessation of CSII (mean glucose 12.7 +/- 0.6 mmol/l after vs 20 +/- 1.5 mmol/l before, P less than 0.005). Maximum incremental C-peptide response improved both to glucagon (214 +/- 32 after vs 134 +/- 48 pmol/l before, P = 0.05) and to glucose iv bolus injection (284 +/- 53 vs 113 +/- 32 pmol/l, P less than 0.05). Peak insulin response, measured after iv glucose infusion, also tended to be higher in the post-CSII test (42 +/- 18 vs 22 +/- 5.6 mU/l). Basal and stimulated proinsulin concentrations were high relative to C-peptide levels during the pre-treatment period, but returned to normal after CSII.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Improved beta-cell function after intensive insulin treatment in severe non-insulin-dependent diabetes. 329 39

Insulin resistance is a characteristic feature of non-insulin dependent diabetes mellitus (NIDDM) due to target tissue defects in insulin action. Abnormalities of cellular insulin action can be divided into receptor and post-receptor defects. Patients with impaired glucose tolerance are insulin resistant due to decreased insulin receptors resulting in decreased insulin sensitivity and rightward shifted in vivo dose response curves. Patients with NIDDM are insulin resistant due to a combination of receptor and post-receptor defects. The greater the severity of the diabetes (greater fasting hyperglycemia) the greater the post-receptor defect, and in those patients with more significant fasting hyperglycemia the post-receptor defect is the predominant abnormality leading to the insulin resistant state. At least one of the abnormalities underlying this post-receptor defect involves a decrease in glucose transport system activity in freshly isolated adipocytes. This defect in glucose transport, is not expressed in cultured fibro-blasts, indicating that the abnormality in glucose disposal seen in vivo and in glucose transport seen in freshly isolated cells is an acquired phenomenon. Consistent with this, the post-receptor defect is partially reversible by insulin therapy, which leads to a 50-70% reversal of the reduced rates of in vivo glucose disposal and in vitro glucose transport. Insulin resistance also exists in poorly controlled IDDM patients, due to a postreceptor defect in insulin action. This insulin resistance is not present in well controlled IDDM patients, and is completely reversible when poorly controlled patients are treated with intensive insulin therapy. Insulin is produced in the pancreatic beta cell as the primary biosynthetic product preproinsulin. This peptide is rapidly converted to proinsulin (MW approximately 9000). Proinsulin is converted to insulin (MW approximately 6000) plus C-peptide in the secretory granule with a small amount (approximately 5 percent) of the proinsulin remaining unconverted. After a brief time in the peripheral circulation (half-life six to 10 minutes), insulin interacts with target tissues to exert its biologic effects. One of insulin's major biologic effects is the promotion of overall glucose metabolism, and abnormalities of this aspect of insulin action can lead to a number of important clinical and pathophysiologic states including Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM). Since insulin travels from the beta cell through the circulation to the target tissues, abnormalities at any of these loci can influence the ultimate action of the hormone. These abnormalities, all
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PMID:Insulin resistance in non-insulin dependent (type II) and insulin dependent (type I) diabetes mellitus. 389 63

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) modulates the metabolic and mitogenic effects of IGFs. Although IGFBP-1 levels are abnormally high in insulin-dependent diabetes (IDDM), relatively little is known in NIDDM; conflicting data have suggested both high and low levels. We investigated whether treatment modifies IGFBP-1 levels in two groups of NIDDM patients. Study 1 examined fasting concentrations in groups of patients with NIDDM, comparable except for treatment type (sulfonylurea, n = 23; once daily insulin, n = 15; sulfonylurea plus once daily insulin, n = 14; multiple insulin injections, n = 9) and 25 nondiabetic subjects. In sulfonylurea-treated patients there were markedly reduced plasma IGFBP-1 concentrations (median, interquartile range in parentheses): control, 61.0 (36-96) micrograms/L; sulfonylureas alone, 31.5 (21-61) micrograms/L (P < 0.01); and sulfonylureas plus insulin, 31.5 (9-53) micrograms/L (P < 0.01). Once daily insulin was associated with values similar to those in the control group [62.0 (27-103) micrograms/L; P = NS], whereas IGFBP-1 levels were higher with multiple insulin injection therapy [156.0 (71-184) micrograms/L; P < 0.05]. Proinsulin levels were higher in sulfonylurea-treated patients, but there was no significant correlation between IGFBP-1 and proinsulin within any individual group. Study 2 examined the effects of treatment on the dynamics of IGFBP-1 levels between 0800-1900 h. In control subjects (n = 8), levels fell from 0800 h (mean +/- SEM, 22.4 +/- 5.2 micrograms/L) to 1000 h (14 +/- 5.2 micrograms/L), followed by a rise, more rapid after food, to a peak at 1240 h (20.6 +/- 3.7 micrograms/L). Levels then declined until 1500 h (10.7 +/- 2.9 micrograms/L), with a further postprandial peak at 1840 h (23.1 +/- 3.2 micrograms/L). Sulfonylurea therapy (n = 6) resulted in a complete loss of this pattern, with a marked fall in IGFBP-1 from 0800 h (22 +/- 2.7 micrograms/L) to less than 7 micrograms/L for the remainder of the study (area under the curve, 1150-1400 h, P < 0.001 vs. control). By contrast, in metformin-treated patients (n = 7), neither IGFBP-1 levels nor postprandial peaks were significantly different from those in the control group. Our findings suggest that in patients with NIDDM, the regulation of IGFBP-1 is markedly influenced by the choice of treatment.
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PMID:Choice of treatment affects plasma levels of insulin-like growth factor-binding protein-1 in noninsulin-dependent diabetes mellitus. 753 8

Glucose-dependent insulinotropic polypeptide (GIP) plays an important role in the regulation of postprandial insulin secretion and proinsulin gene expression of pancreatic beta-cells. This study demonstrates the molecular cloning of a cDNA for the GIP-receptor from a human insulinoma lambda gt11 cDNA library. The cloned cDNA encoded a seven transmembrane domain protein of 466 amino acids which showed high homology (41%) to the human glucagon-like peptide 1 (GLP-1) receptor. Homology to the GIP receptor from rat or hamster was 79% and 81%, respectively. When transfected stably into fibroblast CHL-cells a high affinity receptor was expressed which coupled to the adenylate cyclase with normal basal cAMP and increasing intracellular cAMP levels under stimulation with human GIP-1-42 (EC50 = 1.29 x 10(-13) M). The receptor accepted only human GIP 1-42 (Kd = 1.93 +/- 0.2 x 10(-8) M) and porcine truncated GIP 1-30 (Kd = 1.13 +/- 0.1 x 10(-8) M) as high affinity ligands. At 1 microM, exendin-4 and (9-39)amide weakly reduced GIP-binding (25%) whereas secretin, glucagon, glucagon-like peptide-1, vasoactive intestinal polypeptide, peptide histidine-isoleucine, and pituitary adenylyl cyclase activating peptide were without effect. In transfected CHL cells, GIP-1-42 did not increase intracellular calcium. Northern analysis revealed one transcript of human GIP receptor mRNA with an apparent size of 5.5 kb. The exact understanding of GIP receptor regulation and signal transduction will aid in the understanding of the incretin hormone's failure to exert its biological action at the pancreatic B-cell in type II diabetes mellitus.
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PMID:Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. 758 26

The monomethyl ester of succinic acid (SME) was recently proposed as a novel tool for stimulation of proinsulin biosynthesis and insulin release in animal models of non-insulin-dependent diabetes mellitus. In the present study, either saline or SME (14 mmol/day) was infused for 3 days to control rats, animals injected with streptozotocin during the neonatal period, and Goto-Kakizaki rats with inherited diabetes. The infusion of SME failed to correct the anomalies found in the islets of diabetic rats, namely, a decreased activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase, a low insulin content, and an impaired secretory response to various nutrient secretagogues including D-glucose, 2-ketoisocaproate, and the combination of L-leucine and L-glutamine. These findings raise the question of whether a more prolonged administration of SME is required to raise the insulin store and improve the secretory potential of the endocrine pancreas in animals with type 2 diabetes.
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PMID:Enzymatic and secretory activities in pancreatic islets of non-insulin-dependent diabetic rats after short-term infusion of succinic acid monomethyl ester. 771 Jul 67

We previously demonstrated in the rat that long term exposure to fatty acids inhibits B-cell function in vivo and in vitro. To further assess the clinical significance of these findings, we tested in human islets the effects of fatty acids on glucose-induced insulin release and biosynthesis and on pyruvate dehydrogenase (PDH) activity. Human islets were obtained from the beta-Cell Transplant Unit (Brussels, Belgium). Exposure to 0.125 mmol/L palmitate or oleate for 48 h during tissue culture (RPMI-1640 and 5.5 mmol/L glucose) inhibited the postculture insulin response to 27 mmol/L glucose by 40% and 42% (P < 0.01 for difference). Inhibition was partly prevented by coculture with 1 mumol/L etomoxir, a carnitine-palmitoyl-transferase-I inhibitor (P < 0.05 for effect of etomoxir). Inhibitory effects on glucose-induced insulin secretion by previous palmitate were additive to the inhibitory effects exerted by previous high glucose (11 and 27 mmol/L). Palmitate-induced inhibition of insulin secretion was evident after exposure to 25 mumol/L added fatty acid. The insulin content of islets exposed to fatty acids was significantly reduced, and glucose-induced proinsulin biosynthesis was inhibited by 59% after palmitate addition and by 51% after oleate exposure (P < 0.01). These effects were partly prevented by etomoxir (P < 0.05). The activity of PDH in mitochondrial extracts of islets preexposed for 48 h to palmitate was decreased by 35% (P < 0.05) vs. that in control islets, whereas the activity of PDH kinase (which inactivates PDH) was significantly increased in the same preparations (P < 0.05). The effects of ketones were tested by 48-h exposure to beta-hydroxybutyrate (beta-D-OHB). Ten millimoles of D-beta-OHB per L inhibited the subsequently tested insulin response to 27 mmol/L glucose by 56% (P < 0.001). Half-maximal inhibitory effects of D-beta-OHB on insulin secretion and insulin content were seen at concentrations between 0.5-2.5 mmol/L. Inhibition by D-beta-OHB was partially reversed by etomoxir, whereas exposure to D-beta-OHB failed to affect PDH and PDH kinase activities. We conclude that fatty acids as well as ketone bodies diminish B-cell responsiveness to glucose in human islets by way of a glucose-fatty acid cycle. Increased plasma concentrations of fatty acids and ketones are likely to be important factors behind the negative influences on B-cell function exerted by a diabetic state in both type 1 and type 2 diabetes.
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PMID:Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. 774 4

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

Improvements in the specificity and sensitivity of assays for insulin-related molecules in the circulation have proved to be necessary and informative in studies of the pathogenesis of non-insulin-dependent diabetes (NIDDM). Of particular interest has been the close relationship between increases in des 31,32 split proinsulin and susceptibility to loss of glucose tolerance and the insulin resistance syndrome. It is suggested that the analogy can be drawn between this measurement and the measurement of HbA1c. The amount of this partially processed precursor of insulin in the circulation indicates the degree of glucose stimulus applied to the beta cell combined with the inherent capacity of the insulin secretory system to respond. Further improvements of the sensitivity and specificity of the assay of proinsulin related molecules are desirable. Deterioration of the early insulin response to oral glucose is a major feature of the loss of glucose tolerance associated with the transition from normal to impaired glucose tolerance and to NIDDM. The extent to which this loss of insulin secretion reflects a major predisposing factor in the aetiology of this type of diabetes or is secondary to glucose toxicity or amyloid accumulation remains to be determined. A relationship between birth weight and impaired glucose tolerance, NIDDM and the insulin resistance syndrome has now been observed in two populations in the UK, in Mexican Americans and in Pima Indians. It is therefore reproducible and applicable to widely differing populations. Much further research is indicated to determine, amongst many questions, how much diabetes is associated with this link and what factors explain it.
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PMID:The pathogenesis of NIDDM. 782 32


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