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

4-Hydroxy-2-nonenal (HNE) is one of the major lipid peroxidation products with cytotoxic and mutagenic activity. It further reacts with protein residues such as histidine to generate stable Michael adducts. To evaluate the status of oxidative stress in the serum of type 2 diabetes mellitus, we constructed a sandwich enzyme-linked immunosorbent assay to measure serum HNE-modified albumin by the use of a specific monoclonal antibody (HNEJ-2) against HNE-histidine adducts as well as an antibody against human serum albumin. Serum of type 2 diabetes outpatients revealed significantly higher levels of HNE-modified albumin (736.1 +/- 34.2 pmol/ml, n = 54) than the matched nondiabetics (611.4 +/- 39.1 pmol/ml, n = 30; means +/- SEM; p = 0.018). However, no significant correlation was observed in diabetic outpatients between the levels of HNE-modified albumin and clinical parameters such as fasted blood glucose, HbA1c, diabetes duration, or complications. Our data demonstrated the increased formation of serum HNE-modified albumin in type 2 diabetic outpatients in the milieu between liver and vascular lumina, indicating the presence of oxidative stress.
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PMID:Serum 4-hydroxy-2-nonenal-modified albumin is elevated in patients with type 2 diabetes mellitus. 1121 73

The objective of this study was to investigate possible defects in the insulin sensitivity and/or the acute insulin response in a group of Mexican patients displaying early-onset type 2 diabetes and to evaluate the contribution of mutations in three of the genes linked to maturity-onset diabetes of the young. We studied 40 Mexican patients with an age of diagnosis between 20 and 40 yr in which the insulin sensitivity as well as the insulin secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to maturity-onset diabetes of the young was carried out by PCR-single strand conformation polymorphism analysis. A low insulin secretory capacity (AIRg = 68.5 +/- 5 muU/mL.min) and a near-normal insulin sensitivity (3.43 +/- 0.2 min/muU.mL x 10(4)) were found in these patients. Among this group we found two individuals carrying missense mutations in exon 4 of the hepatocyte nuclear factor-1alpha (HNF-4alpha) gene (Asp(126)-->His/Tyr and Arg(154)-->Gln, respectively) and one carrying a nonsense mutation in exon 7 of the HNF-1alpha gene (Gln(486)-->stop codon); 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. A defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 yr of age. Mutations in either the HNF-1alpha or the HNF-4alpha genes are present among the individuals who develop early-onset diabetes in our population. These particular sequence changes have not been previously reported and therefore represent putative new mutations. Even in the absence of endogenous hyperinsulinemia, insulin resistance is associated with an adverse lipid profile.
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PMID:Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population. 1123 4

Membrane peptidases are a group of ectoenzymes with a broad functional repertoire. In protein metabolism, their importance is well known, especially in peptide degradation and amino acid scavenging at the intestinal and renal brush border. However, they also perform more subtle tasks; not only do they provide or extinguish signals by cleaving exterior peptide mediators, but they also may function as receptors or participate in signal transduction or in adhesion. Dipeptidyl peptidase IV (DPPIV), which is identical to the lymphocyte surface glycoprotein CD26, is unique among these peptidases because of its ability to liberate Xaa-Pro and less efficiently Xaa-Ala dipeptides from the N-terminus of regulatory peptides. It occurs in the plasma membrane as a homodimer with a total molecular mass of 22-240 KdA and the C-terminal domain probably forms on alpha/beta hydrolase fold. In addition to, but independent of its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase. The in vivo expression on epithelial, endothelial and lymphoid cells of DPPIV is compatible with a role as physiological regulator of a number of peptides that serve as biochemical reporters between and within the immune and neuroendocrine system. Surprisingly, not cytokines with a N-terminal Xaa-Pro motif, but a number of chemokines have recently been identified as substrates. Despite DPPIV mediates only a minimal N-terminal truncation, important alterations in chemokine activities and receptor specificitIes were observed in vitro together with modified inflammatory and antiviral responses. Most probably the great flexibility of the N-terminus of a number of chemokines facilitates the accessibIlity to the catalytic site of DPPIV. Other known substrates which are subject in vitro to receptor-specific changes induced by DPPIV truncation include neuropeptides such as substance P, peptidE YY and neuropeptide Y. On the other hand, DPPIV mediated cleavage of the N-terminal His-Ala or Tyr-Ala dipeptides from circulating incretin hormones like, glucagon-like peptides (GLP)-1 and -2, gastric inhibitory polypeptide (GIP), all members of the enteroglucagon/GRF superfamily, results in their biological inactivation in vitro and in vivo. Administration of specific DPPIV inhibitors closes this pathway of incretin degradation and greatly enhances insulin secretion. The improved glucose tolerance in several animal models for type II diabetes points to specific DPPIV inhibition as a pharmaceutical approach for type 2 diabetes drug development.
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PMID:Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery? 1128 88

Case presentations are one of the most instructive formats for learning. They allow the healthcare practitioner to identify and discuss patients who are at risk for a disease and then discuss appropriate therapy. Two patients who have dyslipidemia and are at risk for a coronary event are described here, along with treatment goals and options, audience responses, and discussions of appropriate therapy choices. Both patients require aggressive lipid management. One has had an angioplasty with placement of a stent. His case is an example of a patient at risk for a secondary coronary event; we refer to these cases as secondary-prevention patients. The other patient has high blood pressure and type 2 diabetes; her risk for a future coronary event based on Framingham risk data is greater than 20% in 10 years and therefore her risk for a future coronary event is equal to someone with established coronary heart disease (CHD). Her case is an example of what we refer to as a primary-prevention patient at high risk. Several large-scale primary- and secondary-prevention trials have demonstrated that aggressive lipid management can reduce the risk of future coronary events. In this supplement, we review some of those trials, the new guidelines, the concept of CHD-equivalent risk, and we will discuss the Framingham risk scoring system to predict the 10-year risk of coronary events in individual patients.
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PMID:Identifying all suspects: case studies. 1151 17

A 48-year-old man with a 14-year history of type 2 diabetes with proliferative diabetic retinopathy and distal symmetrical diabetic polyneuropathy visited our hospital. Eight months later, he subacutely developed difficulty in both shoulder movement and trouble standing up from a squatting position. This was accompanied by severe bilateral shoulder and thigh pain. Magnetic resonance imaging of the brain, cervical and lumbar spine, computed tomography of the shoulder and X-ray films of the cervical spine and shoulder revealed no abnormality. Cerebrospinal fluid showed a mild elevation of protein (0.93 g/l) without cell infiltration. Antiganglioside antibodies and point mutation of mitochondrial DNA at position 3243 were not found. Neuropathology of the sural nerve showed a moderate myelinated fiber loss, active axonal degeneration, but onion-bulb formation, endoneurial or epineurial vasculitis were not observed. Electromyography revealed neurogenic changes in the proximal upper limb muscles. Nerve conduction studies revealed mild bilateral slowing in nerve conduction velocity in both of the upper and lower limbs. The diagnosis of this patients was suspected to be a proximal diabetic neuropathy (diabetic amyotrophy). The pain and muscle weakness had persisted more severely in the shoulder than in the thigh throughout the clinical course. His unbearable symptoms could be partially alleviated by an administration of a selective serotonin reuptake inhibitor, fluvoxamine maleate. Proximal diabetic neuropathy is a rare disabling type of neuropathy, which is characterized with subacute bilateral muscle weakness and wasting in the proximal part of the lower limbs. The involvement of the scapulohumeral region observed in this case is very unusual in proximal diabetic neuropathy.
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PMID:A suspected case of proximal diabetic neuropathy predominantly presenting with scapulohumeral muscle weakness and deep aching pain. 1153 31

The use of glucagon-like peptide-1 (GLP-1) as a routine treatment for type 2 diabetes mellitus is undermined by its short biological half-life. A cause of degradation is its cleavage at the N-terminal HAE sequence by the enzyme dipeptidyl peptidase IV (DPP IV). To protect from DPP IV, we have studied the biological activity of a GLP-1 analog in which 6-aminohexanoic acid (Aha) is inserted between histidine and alanine at positions 7 and 8. We have compared the biological activity of this new compound, GLP-1 Aha(8), with the previously described GLP-1 8-glycine (GLP-1 Gly(8)) analog. GLP-1 Aha(8) (10 nM) was equipotent with GLP-1 (10 nM) in stimulating insulin secretion in RIN 1046-38 cells. As with GLP-1 Gly(8), the binding affinity of GLP-1 Aha(8) for the GLP-1 receptor in intact Chinese hamster ovary (CHO) cells expressing the human GLP-1 receptor (CHO/GLP-1R cells) was reduced (IC(50): GLP-1, 3.7 +/- 0.2 nM; GLP-1 Gly(8), 41 +/- 9 nM; GLP-1 Aha(8), 22 +/- 7 nM). GLP-1 Aha(8) was also shown to stimulate intracellular cAMP production 4-fold above basal at concentrations as low as 0.5 nM. However, it exhibited a higher ED(50) when compared to GLP-1 and GLP-1 Gly(8) (ED(50): GLP-1, 0.036 +/- 0.002 nM, GLP-1 Gly(8), 0.13 +/- 0.02 nM, GLP-1 Aha(8), 0.58 +/- 0.03 nM). A series of D-amino acid-substituted GLP-1 compounds were also examined to assess the importance of putative peptidase-sensitive cleavage sites present in the GLP-1 molecule. They had poor binding affinity for the GLP-1 receptor, and none of these compounds stimulated the production of intracellular cAMP in CHO/GLP-1R cells or insulin secretion in RIN 1046-38 cells. GLP-1 Aha(8) (24 nmol/kg) administered sc to fasted Zucker (fa/fa) rats (mean blood glucose, 195 +/- 32 mg/dl) lowered blood glucose levels to a nadir of 109 +/- 3 mg/dl, and it remained significantly lower for 8 h. Matrix-assisted linear desorption ionization-time of flight mass spectrometry of GLP-1 Aha(8) incubated with DPP IV (37 C, 2 h) did not exhibit an N-terminal degradation product. Taken together, these results show that insertion of Aha after the 7 position in GLP-1 produces an effective, long-acting GLP-1 analog, which may be useful in the treatment of type 2 diabetes mellitus.
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PMID:Insertion of an N-terminal 6-aminohexanoic acid after the 7 amino acid position of glucagon-like peptide-1 produces a long-acting hypoglycemic agent. 1156 11

Olanzapine, a serotonin-dopamine-receptor antagonist, is an atypical antipsychotic agent used to treat schizophrenia and other psychotic disorders. It is preferred over older antipsychotics because of its relatively low frequency of sedation, orthostatic hypotension, extrapyramidal symptoms, and anticholinergic side effects. A 45-year-old man with well-controlled type 2 diabetes mellitus experienced an abrupt worsening of his diabetes after 3 years of olanzapine therapy His hemoglobin A1c (HbA1c) level rose from a baseline of 5.9-6.2% to 12.5%. Discontinuation of olanzapine by means of a 3-month taper resulted in a reduction in HbA1c to pretreatment levels. Although cases of olanzapine-induced hyperglycemia have been documented in the literature, this complication has not been reported in a patient maintained on therapy for this duration. Clinicians should be aware of this possible complication in patients receiving long-term olanzapine therapy.
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PMID:Dramatic worsening of type 2 diabetes mellitus due to olanzapine after 3 years of therapy. 1171 19

A 77-year-old man was in good health until he complained of fatigue 3 weeks before presentation. Two weeks before admission, he developed gradually worsening shortness of breath. One week before admission, he developed a cough that initially was nonproductive but later was associated with hemoptysis.His past medical history was remarkable for a history of colon cancer (Dukes' stage III), for which he underwent a hemicolectomy and treatment with adjuvant chemotherapy in 1993. He had a myocardial infarction in 1986 and underwent coronary artery bypass surgery in 1999. He also had a history of hypertension, type 2 diabetes, and gout. He smoked in the past but had stopped more than 30 years ago.He was initially evaluated by his primary care physician, who noted that he complained of diaphoresis but denied fevers, chills, or contact with others who were ill. His physical examination was remarkable for bilateral crackles that were more pronounced on the right. A chest radiograph demonstrated bilateral pulmonary infiltrates (Figure 1). He was treated with amoxicillin. The next day, however, his physician noted that his dyspnea had worsened and that his oxygen saturation on room air was poor. He was therefore admitted for further evaluation. The amoxicillin was discontinued, and he was treated with levofloxacin, followed by ceftriaxone and azithromycin as his pulmonary status continued to deteriorate. He received intravenous diuretic agents, which failed to improve his respiratory status. During the initial phase of hospitalization, he was anemic, with a hematocrit of 21.3%. His serum creatinine level, which had been 1.0 mg/dL in 1999, was now 2.5 mg/dL. Urinalysis was remarkable for the presence of numerous red blood cells. His oxygen requirement increased, and he eventually required a 100% nonrebreather mask. A computed tomographic scan of the chest demonstrated prominent alveolar opacities throughout the right upper, middle, and lower lobes, with similar opacities in the left upper and left lower lobes (Figure 2). An echocardiogram showed an ejection fraction of 50%, as well as mild mitral regurgitation. Serologies were remarkable for an antinuclear antibody titer of 1:320 and a P-antineutrophil cytoplasmic antibody (P-ANCA) titer of greater than 1:320. C-ANCA was negative. Anti-glomerular basement membrane and anti-human immunodeficiency virus antibodies were undetectable.
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PMID:Cases from the medical grand rounds of the Osler Medical Service at Johns Hopkins University. 1207 15

A 20-year-old Japanese man was admitted to our hospital because of thirst and weight loss. His fasting plasma glucose, glycated hemoglobin, and urinary C-peptide were 262 mg/dl, 13.6%, and 44.8 microg/day, respectively, and the autoimmune antibodies related to type 1 diabetes were negative. Chromosome analysis of his peripheral blood lymphocytes showed a mos45,XY,der(14;14)(q10;ql0)[129]/ 46,XY,+14, der(14;14)(q10;q10)[1] karyotype. His parents were karyotypically normal. Microsatellite marker analysis on chromosome 14 demonstrated mosaic maternal segmental isodisomy for 14q21-q24. Although the parents had normal glucose regulation, the patient who finally returned to impaired glucose tolerance and his mother both have a deficiency in early postprandial insulin secretion. Since obesity was mild (body mass index, 24.1 kg/m2) and he was relatively young for type 2 diabetes, we speculated that his isodisomy 14 may have been involved in the onset of diabetes mellitus in this patient.
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PMID:Maternal uniparental disomy for chromosome 14 with diabetes mellitus. 1232 99

The incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) has been deemed of considerable importance in the regulation of blood glucose. Its effects, mediated through the regulation of insulin, glucagon, and somatostatin, are glucose-dependent and contribute to the tight control of glucose levels. Much enthusiasm has been assigned to a possible role of GLP-1 in the treatment of type 2 diabetes. GLP-1's action unfortunately is limited through enzymatic inactivation caused by dipeptidylpeptidase IV (DPP IV). It is now well established that modifying GLP-1 at the N-terminal amino acids, His(7) and Ala(8), can greatly improve resistance to this enzyme. Little research has assessed what effect Glu(9)-substitution has on GLP-1 activity and its degradation by DPP IV. Here, we report that the replacement of Glu(9) of GLP-1 with Lys dramatically increased resistance to DPP IV. This analogue, (Lys(9))GLP-1, exhibited a preserved GLP-1 receptor affinity, but the usual stimulatory effects of GLP-1 were completely eliminated, a trait duplicated by the other established GLP-1-antagonists, exendin (9-39) and GLP-1(9-36)amide. We investigated the in vivo antagonistic actions of (Lys(9))GLP-1 in comparison with GLP-1(9-36)amide and exendin (9-39) and revealed that this novel analogue may serve as a functional antagonist of the GLP-1 receptor.
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PMID:Lys9 for Glu9 substitution in glucagon-like peptide-1(7-36)amide confers dipeptidylpeptidase IV resistance with cellular and metabolic actions similar to those of established antagonists glucagon-like peptide-1(9-36)amide and exendin (9-39). 1476 80


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