Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that recombinant human IGF-I (rhIGF-I) is a potential therapeutic agent in diabetes mellitus. It is known to have glucose-lowering effects in normal individuals, in patients with non-insulin-dependent diabetes (NIDDM) and in extreme insulin-resistant states. IGF-binding proteins (IGFBPs) have the potential to affect the biological activity of rhIGF-I. We have studied the effect of infused rhIGF-I on IGFBP-1 and IGFBP-3 in a patient with Mendenhall's syndrome, a rare insulin-resistant state. During an infusion of 20 mg rhIGF-I, glucose concentrations fell from 44.1 +/- 7.2 to 31.5 +/- 7.2 (S.E.M.) mmol/l (P = 0.001), and insulin and C-peptide levels fell from 920 +/- 62 to 542 +/- 45 mU/l (P = 0.008) and 5466 +/- 633 to 3071 +/- 297 pmol/l (P = 0.02) respectively. Significant lowering of phosphate, magnesium and alkaline phosphatase concentrations was also noted. IGF-I levels rose from 48 +/- 10.2 to 410 +/- 50.1 micrograms/l (P = 0.001), and those of IGF-II fell from 279.8 +/- 8.3 to 104.3 +/- 7.9 micrograms/l (P = 0.001). IGFBP-1 concentrations did not significantly change during the infusion but those of IGFBP-3 increased from 1655 +/- 127 to 2197 +/- 334 micrograms/l (P = 0.002), despite a significant fall in GH concentrations from 10.7 +/- 2.6 to 4.1 +/- 1.1 mU/l (P = 0.007), suggesting that IGFBP-3 regulation is also IGF-I-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Response of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) and IGFBP-3 to IGF-I treatment in severe insulin resistance. 751 62

Several studies of diabetes mellitus patients have demonstrated abnormalities in calcium, phosphate and vitamin D metabolism. In an earlier study, the authors reported impaired renal processing of phosphate in spontaneously diabetic GK rats, an animal model of type II diabetes mellitus. In the present study, which represents an extension of the earlier study, vitamin D metabolism and response are examined in 20-week-old GK rats. Serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] was found to be lower in GK rats than in Wistar rats. After intraperitoneal administration of 0.5 micrograms/kg 1,25-(OH)2D, serum calcium increased in GK rats, but not in Wistar rats, while serum phosphate remained unchanged in GK rats, but increased in Wistar rats. Although serum 1,25-(OH)2D rose abruptly in 3 h and decreased thereafter in both GK and Wistar rats, the decrease in serum 1,25-(OH)2D at 6 h was more marked in GK rats than in Wistar rats. Serum 24,25-dihydroxyvitamin D was consistently higher in GK rats than in Wistar rats. Northern blotting and dot blotting with use of a cDNA probe for the 24-hydroxylase gene showed an increased expression of the gene in the kidney of GK rats. These results demonstrate impaired vitamin D metabolism in GK rats. Increased activity of 24-hydroxylase, in addition to impaired phosphate metabolism, may play a role in impaired vitamin D metabolism in GK rats.
 ...
PMID:Impaired vitamin D metabolism and response in spontaneously diabetic GK rats. 756 51

The sequence of events that culminate in the development of diabetes in the fa/fa Zucker diabetic fatty (ZDF) rat is unclear. In the present series of experiments islets from 5 week old prediabetic fa/fa male rats were isolated and their phosphoinositide (PI) hydrolysis and insulin secretory responses compared to those obtained from lean nondiabetic age- and weight-matched control rats. Peak first and second phase insulin secretory responses to 20mM glucose averaged 77 +/- 10 (mean +/- SE, n = 7) and 491 +/- 47 pg/islet/min from lean, nondiabetic control islets. The comparable responses from fa/fa prediabetic rat islets were significantly greater, 264 +/- 51 and 810 +/- 78 pg/islet/min. In a parallel fashion 3H-inositol efflux and inositol phosphate responses from prediabetic rat islets were also greater than comparable control responses. These findings demonstrate that significant increases in the phospholipase C-mediated hydrolysis of islet PI pools and insulin release in response to hyperglycemic stimulation can be detected prior to the emergence of diabetes in the fa/fa ZDF rat. These early changes in beta cell responsiveness to glucose may contribute to the hyperinsulinemia and subsequent insulin resistance characteristic of this animal model of non-insulin dependent diabetes mellitus.
 ...
PMID:Islet phosphoinositide hydrolysis and insulin secretory responses from prediabetic fa/fa ZDF rats. 773 92

There are two types of diabetes mellitus. Type I, insulin-dependent diabetes (IDDM), which becomes manifest before the age of 40, is the result of an absolute deficiency of insulin. Type II, the non-insulin-dependent diabetes (NIDDM), develops in the elderly and is caused by a relative insulin deficiency. Patients with type-I diabetes are prone to the development of ketoacidosis, while type II causes hyperglycaemic, hyperosmolar, nonketotic coma. Apart from these acute metabolic alterations, the long-term complications of diabetes are of concern to the anaesthesiologist. Hypertension, coronary artery disease, renal insufficiency and autonomic neuropathy are common and can result in myocardial ischaemia, cardiovascular instability and gastroparesis, with an increased risk of aspiration. Limited movement of the atlanto-occipital joint can cause difficult intubation. To avoid perioperative metabolic catastrophy, blood glucose concentration should be kept between 6.7 and 10 mmol.l-1 (120-180 mg.dl-1). Hypoglycaemia can result in neurological damage, whereas hyperglycaemia causes impaired wound healing and susceptibility to infections and worsens ischaemic damage to the myocardium and brain. Perioperative diabetes management depends on the severity of the surgical procedure and the type of diabetes. All type-I diabetics, whatever operation being performed, need insulin. The intravenous route is recommended as it allows better adjustment. After determination of the fasting blood glucose level, insulin is given at a dosage of 0.5-1 U.h-1 (at gluc < 11.1 mmol.l-1), 1.5-2 U.h-1 (at gluc 11.1-16.7 mmol.l-1) or 3 U.h-1 (at gluc > 16.7 mmol.l-1). In addition, 5-10 g glucose.h-1 is given. In type-II diabetes the oral antidiabetic drug is withheld. During minor surgery the blood glucose concentration is monitored frequently, and if necessary insulin (with gluc > 13.9 mmol.l-1) or glucose is given. In most cases of major surgery insulin therapy will be necessary. Administration should follow the guidelines listed for type-I diabetes. Whether the intravenous or the subcutaneous route is used for insulin, repeated glucose determinations are mandatory. If ketoacidosis develops the volume depletion is treated with normal saline. For hyperglycaemia and acidosis insulin (3-6 U.h-1) with 10-20 mmol.h-1 potassium phosphate is given. Bicarbonate is only indicated when the serum pH is lower than 7.1. It must be borne in mind that perioperative management of diabetes does not end with postanaesthesia care.
 ...
PMID:[Anesthesia and diabetes mellitus]. 804 63

The mitochondrial enzyme FAD-linked glycerophosphate dehydrogenase (m-GDH) is thought to play a key role in the glucose-sensing mechanism of the insulin-producing B-cell. It catalyses a rate-limiting step of the glycerol phosphate shuttle in pancreatic islets. Its activation by Ca2+ accounts for the preferential stimulation of oxidative glycolysis and, hence, pyruvate oxidation in glucose-stimulated islets. Reduced activity of m-GDH was recently observed in islet, but not liver, homogenates from rats injected with streptozotocin during the neonatal period and in two models of inherited diabetes, i.e. GK rats and db/db mice. In the streptozotocin-injected and GK rats the m-GDH islet defect coincided, in intact islets, with an abnormally low ratio between oxidative and total glycolysis. Decreased activity of m-GDH in T-lymphocytes was also observed in 12 of 32 type 2 (non-insulin-dependent) diabetic patients, but only once among 26 other subjects including 11 healthy volunteers, 9 non-diabetics and 6 patients with either type 1 (insulin-dependent) or symptomatic diabetes. In the T-lymphocytes of type 2 diabetics the m-GDH deficiency occasionally coincided with an abnormally high ratio between glutamate-pyruvate and glutamate-oxaloacetate transaminase activities, as also observed in islets from streptozotocin-injected or GK rats. It is speculated that an islet m-GDH defect could represent a far from uncommon factor contributing to the pathogenesis of type 2 diabetes mellitus.
 ...
PMID:Is type 2 diabetes due to a deficiency of FAD-linked glycerophosphate dehydrogenase in pancreatic islets? 832 24

In the Goto-Kakizaki rat, a new genetic model of NIDDM, insulin response to glucose is selectively impaired. To elucidate the mechanism of this abnormality, we studied the properties of ATP-sensitive K+ channels, the inhibition of which is a key step of insulin secretion induced by fuel substrates, using the patch-clamp technique. The glucose-sensitivity of KATP channels was considerably reduced in GK rats. However, the inhibitory effects of ATP on channel activity and unitary conductance were not significantly different between control and GK rats. Thus, it appears that the impaired insulinotropic action of glucose in beta-cells of GK rats is attributable to insufficient closure of the KATP channels, probably because of deficient ATP production by impaired glucose metabolism. KATP-channel activities in both control and diabetic beta-cells were found to be equally suppressed by glyceraldehyde and 2-ketoisocaproate. These results strongly suggest that the step responsible for the metabolic dysfunction of diabetic beta-cells is located within the glycolytic pathway before glyceraldehyde-3-phosphate or in the glycerol phosphate shuttle.
 ...
PMID:Glucose sensitivity of ATP-sensitive K+ channels is impaired in beta-cells of the GK rat. A new genetic model of NIDDM. 837 84

Physiologically, a postprandial glucose rise induces metabolic signal sequences that use several steps in common in both the pancreas and peripheral tissues but result in different events due to specialized tissue functions. Glucose transport performed by tissue-specific glucose transporters is, in general, not rate limiting. The next step is phosphorylation of glucose by cell-specific hexokinases. In the beta-cell, glucokinase (or hexokinase IV) is activated upon binding to a pore protein in the outer mitochondrial membrane at contact sites between outer and inner membranes. The same mechanism applies for hexokinase II in skeletal muscle and adipose tissue. The activation of hexokinases depends on a contact site-specific structure of the pore, which is voltage-dependent and influenced by the electric potential of the inner mitochondrial membrane. Mitochondria lacking a membrane potential because of defects in the respiratory chain would thus not be able to increase the glucose-phosphorylating enzyme activity over basal state. Binding and activation of hexokinases to mitochondrial contact sites lead to an acceleration of the formation of both ADP and glucose-6-phosphate (G-6-P). ADP directly enters the mitochondrion and stimulates mitochondrial oxidative phosphorylation. G-6-P is an important intermediate of energy metabolism at the switch position between glycolysis, glycogen synthesis, and the pentose-phosphate shunt. Initiated by blood glucose elevation, mitochondrial oxidative phosphorylation is accelerated in a concerted action coupling glycolysis to mitochondrial metabolism at three different points: first, through NADH transfer to the respiratory chain complex I via the malate/aspartate shuttle; second, by providing FADH2 to complex II through the glycerol-phosphate/dihydroxy-acetone-phosphate cycle; and third, by the action of hexo(gluco)kinases providing ADP for complex V, the ATP synthetase. As cytosolic and mitochondrial isozymes of creatine kinase (CK) are observed in insulinoma cells, the phosphocreatine (CrP) shuttle, working in brain and muscle, may also be involved in signaling glucose-induced insulin secretion in beta-cells. An interplay between the plasma membrane-bound CK and the mitochondrial CK could provide a mechanism to increase ATP locally at the KATP channels, coordinated to the activity of mitochondrial CrP production. Closure of the KATP channels by ATP would lead to an increase of cytosolic and, even more, mitochondrial calcium and finally to insulin secretion. Thus in beta-cells, glucose, via bound glucokinase, stimulates mitochondrial CrP synthesis. The same signaling sequence is used in the opposite direction in muscle during exercise when high ATP turnover increases the creatine level that stimulates mitochondrial ATP synthesis and glucose phosphorylation via hexokinase. Furthermore, this cytosolic/mitochondrial cross-talk is also involved in activation of muscle glycogen synthesis by glucose. The activity of mitochondrially bound hexokinase provides G-6-P and stimulates UTP production through mitochondrial nucleoside diphosphate kinase. Pathophysiologically, there are at least two genetically different forms of diabetes linked to energy metabolism: the first example is one form of maturity-onset diabetes of the young (MODY2), an autosomal dominant disorder caused by point mutations of the glucokinase gene; the second example is several forms of mitochondrial diabetes caused by point and length mutations of the mitochondrial DNA (mtDNA) that encodes several subunits of the respiratory chain complexes. Because the mtDNA is vulnerable and accumulates point and length mutations during aging, it is likely to contribute to the manifestation of some forms of NIDDM.(ABSTRACT TRUNCATED)
 ...
PMID:Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. 854 53

We measured lumbar bone mineral density (L2-4 MBMD) in the postmenopausal elderly diabetic women and made comparisons with age-matched controls in terms of the age, body mass index (BMI) and % BMD of age-matched. In addition we evaluated the correlation between BMD and menarche age, menopause age, HbA1c, serum calcium, serum phosphate, serum alkaline phosphatase (S-Alp) and the ratio of urine calcium to urine creatinine (UCa/Cr). Moreover we divided non-insulin dependent diabetic patients (NIDDM) into two groups; the high BMD group and the low BMD group. Serum Alp and the ratio of UCa/Cr were compared in these two groups. The relationships between regimen of therapy and BMD were also analyzed in female NIDDM. There were no significant differences of BMD and background factors between controls and NIDDM. The ratio of UCa/Cr in the high BMD group were significantly less than that in low BMD group (p < 0.05). BMD in NIDDM with retinopathy was lower, but not significantly, than that in NIDDM without retinopathy. The methods of therapy for NIDDM such as diet alone, an oral hypoglycemic agent and insulin did not influence BMD in elderly postmenopausal diabetics. These results indicated that BMD in elderly postmenopausal diabetics are dependent on UCa/Cr and retinopathy.
 ...
PMID:[Bone mineral density in postmenopausal elderly women with type 2 diabetes]. 859 32

Two genes that have potentially important regulatory roles in insulin secretion are both located on chromosome 2q24.1. G-protein-coupled muscarinic potassium channel (GIRK1) is an inwardly rectifying K+ channel that helps to maintain the resting potential and excitability of cells. Mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH) catalyzes a rate-limiting step of the glycerol phosphate shuttle in pancreatic islets. Reduced m-GDH activity has been demonstrated in islets isolated from diabetic subjects compared with islets from nondiabetic control subjects and from the diabetic GK rat. To study the relationship between these candidate genes and NIDDM, we have examined a simple tandem-repeat polymorphism (STRP) close to both the KCN J3 (GIRK1) locus and the m-GDH locus. In a linkage study of three maturity-onset diabetes of the young (MODY) pedigrees, not linked to MODY1, MODY2, or MODY3, a cumulative score of - 9.6 at a recombination fraction of theta = 0 excluded linkage. In a population-association study, no linkage disequilibrium for the STRP was found between 190 unselected NIDDM patients and 60 geographically and age-matched white nondiabetic subjects (chi2 = 1.51 on 3 df, P = 0.68). Thus, mutations involving the genes for GIRK1 or FAD-glycerophosphate dehydrogenase are unlikely to cause MODY, and a common mutation in either gene is unlikely to contribute to NIDDM in whites. These data do not exclude mutations in some families or other ethnic groups.
 ...
PMID:Mitochondrial FAD-glycerophosphate dehydrogenase and G-protein-coupled inwardly rectifying K+ channel: No evidence for linkage in maturity-onset diabetes of the young or NIDDM. 862 Oct 16

We investigated the effect of insulin on urinary excretion of phosphate in type II diabetes mellitus (DM) with respect to the absence or presence of renal insufficiency. A euglycemic-hyperinsulinemic clamp was performed in 37 type II DM patients. Subjects were divided into two groups: group A consisted of patients with serum creatinine levels less than 1.5 mg/dL (n = 22), and group B consisted of patients with serum creatinine levels of 1.5 mg/dL or greater (n = 15). Blood and urine samples were collected at the beginning and end of the clamp, and urinary excretion of phosphate was evaluated by calculating fractional excretion (FE-P). Tissue sensitivity to insulin in the whole body was expressed as the glucose infusion rate (M value) and that divided by steady-state plasma insulin levels (M/I ratio) during the last 30 minutes of the clamp. FE-P in group A patients significantly decreased during the clamp (from 9.46 +/- 0.67% before the clamp to 7.12 +/- 0.73% after the clamp, P < .004), whereas FE-P in group B patients did not change significantly during the clamp. The percent decrease of FE-P (decrease of FE-P during the clamp divided by FE-P before the clamp) in group A patients was significantly higher than in group B patients (22.5 +/- 7.0% and 2.5 +/- 5.1 %, respectively, P < .04). In all 37 patients, the percent decrease of FE-P was negatively correlated with blood urea nitrogen ([BUN] r = -.36, P < .05), serum creatinine (r = -.34, P < .05), and serum beta2-microglobulin (r = -.44, P < .01) and positively correlated with creatinine clearance (r = .570, P < .004), but it was not correlated with the M value or M/I ratio. These results showed that the kidneys of diabetic patients with renal insufficiency are insulin-insensitive in terms of phosphate transport, and the insulin insensitivity is related to the glomerular filtration rate but not to systemic insulin insensitivity. The percent decrease of FE-P on clamp study could be useful for assessing the insulin insensitivity of the kidney, which probably occurs primarily in the renal tubules.
 ...
PMID:Effect of insulin on urinary phosphate excretion in type II diabetes mellitus with or without renal insufficiency. 863 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>