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)

Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis that, like glucagon-like peptide 1(7-36) amide (tGLP-1), has a functional profile of possible therapeutic value for type 2 diabetes. Both incretin hormones are rapidly inactivated in plasma by the exopeptidase dipeptidyl peptidase (DPP) IV. The present study examined the ability of NH2-terminal modification of human GIP to protect from plasma degradation and enhance insulin-releasing and antihyperglycemic activity. Degradation of GIP by incubation at 37 degrees C with purified DPP IV was clearly evident after 4 h (54% intact). After 12 h, >60% of GIP was converted to GIP(3-42), whereas >99% of NH2-terminally modified Tyr1-glucitol GIP remained intact. Tyr1-glucitol GIP was similarly resistant to serum degradation. The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Tyr1-glucitol GIP were examined in Wistar rats after intraperitoneal injection of either peptide (10 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly lower and insulin concentrations higher after both peptides compared with glucose alone. More importantly, individual glucose values at 15 and 30 min together with the areas under the curve (AUCs) for glucose were significantly lower after administration of Tyr1-glucitol GIP compared with GIP (AUC 255 +/- 33 vs. 368 +/- 8 mmol x l(-1) x min(-1), respectively; P < 0.01). This was associated with a significantly greater and more protracted insulin response after Tyr1-glucitol GIP than GIP (AUC 773 +/- 41 vs. 639 +/- 39 ng x ml(-1) x min(-1); P < 0.05). These data demonstrate that Tyr1-glucitol GIP displays resistance to plasma DPP IV degradation and exhibits enhanced antihyperglycemic activity and insulin-releasing action in vivo.
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PMID:NH2-terminally modified gastric inhibitory polypeptide exhibits amino-peptidase resistance and enhanced antihyperglycemic activity. 1010 92

Genetic studies have shown that mutations in the gene encoding hepatocyte nuclear factor (HNF)-4alpha, a member of the steroid/thyroid hormone receptor superfamily, give rise to early-onset type 2 diabetes (MODY1). The functional properties of mutant HNF-4alpha proteins and the molecular mechanisms by which they impair insulin secretion are largely unknown. In the present study, we have investigated transcriptional activation, DNA binding properties, and protein dimerization activity of three HNF-4alpha missense mutations--HNF4(R127W), HNF4(V255M), and HNF4(E276Q)--that have been associated with type 2 diabetes. We demonstrate that HNF4(E276Q) has lost its ability to bind to HNF-4 consensus binding sites and activate transcription. HNF4(E276Q) had no effect on the functional activity of wild-type HNF-4alpha in the pancreatic beta-cell line HIT-T15, but it exhibited weak dominant-negative activity in other cell types. Analysis of HNF4(E276Q) protein showed that it exists in two forms: a full length 54-kDa protein and a 40-kDa COOH-terminal protein lacking the NH2-terminal transactivation domain and the DNA binding domain. Immunoprecipitation experiments indicate that this truncated protein can bind to wild-type HNF-4alpha and may be responsible for the weak dominant-negative effects seen in these cells. In addition, we show that the transcriptional transactivation of HNF4(R127W) and HNF4(V255M) is indistinguishable from that of wild-type HNF-4alpha, suggesting that they are sequence polymorphisms. Our results demonstrate that HNF4(E276Q) is a loss-of-function mutation and that it identifies glutamic acid 276 in alpha-helix 8 of the ligand-binding domain of HNF-4alpha protein as a critical residue for DNA binding, transcriptional activation, and protein stability in vivo.
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PMID:Functional characterization of the MODY1 gene mutations HNF4(R127W), HNF4(V255M), and HNF4(E276Q). 1038 54

Peroxisome proliferator-activated receptor (PPAR)-gamma is a major regulator of adipogenesis and insulin sensitivity. The PPAR-gamma gene generates two isoforms through alternative splicing, PPAR-gamma1 and -gamma2, the latter having an additional stretch of 28 amino acids at its NH2-terminus in the ligand-independent activation domain. This extension renders PPAR-gamma2 more sensitive to insulin action. Since there is a Pro12Ala substitution in this domain, we tested whether it is related to type 2 diabetes or insulin resistance. Therefore, 131 type 2 diabetic patients and 312 normoglycemic control subjects were screened for the presence of the mutation and for major clinical and metabolic features. The frequency of the mutation did not differ significantly between diabetic patients and control subjects. BMI, insulin, and other metabolic and anthropometric variables were also not associated with the mutation. Although the study was carried out on a sufficiently large sample, the conclusions do not support a major role for the Pro12Ala substitution of the PPAR-gamma gene in the etiology of type 2 diabetes.
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PMID:Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. 1038 55

Incubation of bovine aortic endothelial cells (BAECs) with erythrocytes from patients with type 2 diabetes induced an increase in endothelin 1 (ET-1) production. The effect of erythrocytes on ET-1 synthesis was dependent on glycemic control. ET-1 levels after incubation with erythrocytes derived from patients with HbA(1c) levels <6% were just half the levels observed after incubation with erythrocytes from patients with HbA(1c) levels >8%. Nepsilon-(carboxymethyl)lysine (CML)-containing protein isolated from patients' erythrocytes induced ET-1, and CML-containing protein-dependent ET-1 induction was blocked by the recombinant decoy peptide soluble receptor for advanced glycation end products (AGEs), which comprises the NH2-terminal Ig domain of the receptor for AGEs. In vitro-generated AGEs induced ET-1 mRNA transcription (nuclear run-on assay and Northern blot) in a time- and dose-dependent manner. Transient transfection of BAECs with a chimeric construct containing the 5' promoter region of the ET-1 gene linked to a reporter gene confirmed that AGE induced ET-1 promoter activity. Electrophoretic mobility shift assay confirmed AGE-inducible binding of members of the nuclear factor-kappab (NF-kappaB) family to a potential binding site at -2,090 bp. Binding was functionally significant because overexpression of the cytoplasmic inhibitor of NF-kappaB or deletion of the NF-kappaB binding site reduced ET-1 induction, whereas overexpression of NF-kappaB p65 induced ET-1 even in the absence of AGEs. Thus, ET-1 transcription is controlled by the AGE-inducible redox-sensitive transcription factor NF-kappaB.
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PMID:Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells. 1096 41

Amino acid catabolism and urea synthesis are increased in type 2 diabetes mellitus in poor metabolic control. In different catabolic conditions, prostaglandins (PGs) of the E series produced metabolic effects on nitrogen metabolism, decreasing urea formation. In 10 patients with type 2 diabetes in poor metabolic control, urea synthesis and amino acid to urea nitrogen exchange were measured in the basal state and during an alanine load (6 hours) with 2-hour superinfusion of a PGE1 analog (30 microg/h) or saline in random order. The urea synthesis rate was calculated as the sum of urinary urea excretion and urea accumulation in total body water (TBW); total nitrogen exchange was calculated as the difference between infused amino acid-nitrogen and urea appearance. Plasma alpha-aminonitrogen (alpha-amino-N) increased 100% in response to alanine, to a steady-state without differences in relation to PG superinfusion. The urea synthesis rate (mean +/- SD) was 34.0 +/- 11.4 mmol/h in the basal period and increased to 161.2 +/- 37.0 during alanine + saline and to 113.5 +/- 34.6 during alanine + PG (P < .001). Nitrogen exchange was negative at baseline (-25.0 +/- 9.0 mmol/h). It became moderately positive during alanine + saline (14.6 +/- 25.1) and far more positive during alanine + PG (53.5 +/- 21.4), with the difference due to reduced urea formation. The metabolic effects of PG were not related to differences in insulin and glucagon. We conclude that PGE1 slows the high rate of hepatic urea-N synthesis in poorly controlled type 2 diabetes. Such metabolic effects have therapeutic implications.
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PMID:Systemic prostaglandin E1 infusion and hepatic aminonitrogen to urea nitrogen conversion in patients with type 2 diabetes in poor metabolic control. 1122 38

Impaired processing of pro-islet amyloid polypeptide (proIAPP), the precursor of the beta-cell peptide islet amyloid polypeptide (IAPP) (amylin), has been implicated in islet amyloid formation in type 2 diabetes. The prohormone convertase enzymes PC3 (also known as PC1) and PC2 are localized to beta-cell secretory granules with proIAPP and proinsulin and are responsible for proinsulin processing. To determine whether PC2 might be essential for proIAPP processing, we performed Western blot analysis of freshly isolated islets from normal mice and mice lacking active PC2. As expected, the primary species of IAPP immunoreactivity in islets from wild-type mice was fully processed (4-kDa) IAPP, with only small amounts of the 8-kDa precursor (unprocessed proIAPP) present. Islets from heterozygous PC2 null mice were identical to wild-type animals, suggesting that half the normal complement of PC2 is sufficient for normal proIAPP processing. By contrast, in islets from homozygous PC2 null mice, the predominant IAPP-immunoreactive form was of intermediate size (approximately 6 kDa), with no detectable mature IAPP and slightly elevated amounts of the 8-kDa precursor form present. Thus, in the absence of PC2, proIAPP processing appears to be blocked at the level of a proIAPP conversion intermediate. Immunofluorescence of pancreas sections and immunoblotting using antisera raised to the NH2- and COOH-terminal flanking regions of mouse proIAPP demonstrated that the 6-kDa intermediate form was an NH2-terminally extended proIAPP conversion intermediate (processed only at the COOH-terminus). These data indicate that PC2 is essential for processing of proIAPP at the NH2-terminal cleavage site in vivo and that PC3 is likely only capable of processing proIAPP at the COOH-terminal cleavage site.
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PMID:The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site. 1124 72

In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.
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PMID:Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. 1237 42

The therapeutic potential of glucagon-like peptide-1 (GLP-1) in improving glycaemic control in diabetes has been widely studied, but the potential beneficial effects of glucose-dependent insulinotropic polypeptide (GIP) have until recently been almost overlooked. One of the major problems, however, in exploiting either GIP or GLP-1 as potential therapeutic agents is their short duration of action, due to enzymatic degradation in vivo by dipeptidylpeptidase IV (DPP IV). Therefore, this study examined the plasma stability, biological activity and antidiabetic potential of two novel NH2-terminal Ala2-substituted analogues of GIP, containing glycine (Gly) or serine (Ser). Following incubation in plasma, (Ser2)GIP had a reduced hydrolysis rate compared with native GIP, while (Gly2)GIP was completely stable. In Chinese hamster lung fibroblasts stably transfected with the human GIP receptor, GIP, (Gly2)GIP and (Ser2)GIP stimulated cAMP production with EC(50) values of 18.2, 14.9 and 15.0 nM respectively. In the pancreatic BRIN-BD11 beta-cell line, (Gly2)GIP and (Ser2)GIP (10(-8) M) evoked significant increases (1.2- and 1.5-fold respectively; P<0.01 to P<0.001) in insulinotropic activity compared with GIP. In obese diabetic ob/ob mice, both analogues significantly lowered (P<0.001) the glycaemic excursion in response to i.p. glucose. This enhanced glucose-lowering ability was coupled to a significantly raised (P<0.01) and more protracted insulin response compared with GIP. These data indicate that substitution of the penultimate Ala2 in GIP by Gly or Ser confers resistance to plasma DPP IV degradation, resulting in enhanced biological activity, therefore raising the possibility of their use in the treatment of type 2 diabetes.
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PMID:Improved biological activity of Gly2- and Ser2-substituted analogues of glucose-dependent insulinotrophic polypeptide. 1252 57

Although it is known that diabetic nephropathy is accelerated by hypertension, the mechanisms involved in this process are not clear. In this study we aimed to clarify these mechanisms using male Wistar fatty rats (WFR) as a type 2 diabetic model and male Wistar lean rats (WLR) as a control. Each group was fed a normal or high sodium diet from the age of 6 to 14 weeks. We determined the blood pressure and urinary albumin excretion (UAE). At the end of the study, the expressions of mitogen-activated protein kinases (MAPK) and transforming growth factor-beta1 (TGF-beta1) were examined in the isolated glomeruli by Western blot analysis, and the number of glomerular lesions was determined by conventional histology. High sodium load caused hypertension and a marked increase in UAE in the WFR but not in the WLR. Glomerular volume was increased in the hypertensive WFR. There was no difference among the four groups in the expression of c-Jun-NH2-terminal kinase (JNK). In contrast, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and its upstream regulator, MAPK/ERK kinase 1 (MEK1), were augmented in the hypertensive WFR. Expression of p38 MAPK was increased in the normotensive WFR, and further enhanced in the hypertensive WFR. Moreover, administration of high sodium load to WFR augmented the expression of TGF-beta1. In conclusion, systemic hypertension in WFR accelerates the diabetic nephropathy in type 2 diabetes via MEK-ERK and p38 MAPK cascades. TGF-beta1 is also involved in this mechanism.
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PMID:Hypertension accelerates diabetic nephropathy in Wistar fatty rats, a model of type 2 diabetes mellitus, via mitogen-activated protein kinase cascades and transforming growth factor-beta1. 1273 3

We characterized the novel, rationally designed peptide glucagon-like peptide 1 (GLP-1) receptor agonist H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH2 (ZP10A). Receptor binding studies demonstrated that the affinity of ZP10A for the human GLP-1 receptor was 4-fold greater than the affinity of GLP-1 (7-36) amide. ZP10A demonstrated dose-dependent improvement of glucose tolerance with an ED50 value of 0.02 nmol/kg i.p. in an oral glucose tolerance test (OGTT) in diabetic db/db mice. After 42 days of treatment, ZP10A dose-dependently (0, 1, 10, or 100 nmol/kg b.i.d.; n = 10/group), decreased glycosylated hemoglobin (HbA1C) from 8.4 +/- 0.4% (vehicle) to a minimum of 6.2 +/- 0.3% (100 nmol/kg b.i.d.; p < 0.05 versus vehicle) in db/db mice. Fasting blood glucose (FBG), glucose tolerance after an OGTT, and HbA1C levels were significantly improved in mice treated with ZP10A for 90 days compared with vehicle-treated controls. Interestingly, these effects were preserved 40 days after drug cessation in db/db mice treated with ZP10A only during the first 50 days of the study. Real-time polymerase chain reaction measurements demonstrated that the antidiabetic effect of early therapy with ZP10A was associated with an increased pancreatic insulin mRNA expression relative to vehicle-treated mice. In conclusion, long-term treatment of diabetic db/db mice with ZP10A resulted in a dose-dependent improvement of FBG, glucose tolerance, and blood glucose control. Our data suggest that ZP10A preserves beta-cell function. ZP10A is considered one of the most promising new drug candidates for preventive and therapeutic intervention in type 2 diabetes.
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PMID:Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice. 1297 99


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