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)

Genetic studies suggest a diabetes susceptibility locus on human chromosome 20, near the melanocortin receptor-3 (MC3-R) gene. We examined the MC3-R as a candidate gene for type 2 diabetes in 12 members of a large Maori kindred with multiple affected members. The coding region of the MC3-R gene was sequenced for both diabetic and non-diabetic individuals. Two separate single base pair substitutions were found in the MC3-R coding sequence and these resulted in amino acid changes, Lysine6Threonine and Isoleucine81Valine. Neither of these MC3-R variants tracked with the presence of diabetes. Furthermore, the variant and wild type MC3-R showed similar functional coupling to adenylyl cyclase. A polymorphic marker (D20S32e) close to the human MC3-R (hMC3-R) coding sequence was investigated in a 60-member pedigree for association with diabetes and other metabolic parameters. There was an association between D20S32e genotype and fasting insulin (P=0.0085) and the insulin resistance index, HOMA-R (P=0.0042). An association was also found between genotype and HDL levels during oral glucose tolerance testing (P=0.0037). These associations were independent of BMI, age, gender and diabetes. Our data do not support a role for variations in the coding region of the hMC3-R in the development of type 2 diabetes in this Maori kindred, but suggest that a locus on chromosome 20 q, close to D20S32e, may contribute to both insulin secretion and action in the Maori kindred.
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PMID:Melanocortin-3 receptor gene variants in a Maori kindred with obesity and early onset type 2 diabetes. 1216 Oct 58

The spontaneously diabetic Goto-Kakizaki rat harbors the same defects expressed in human type 2 diabetes. It is not clear, however, whether stress factors emanating from the adrenal glands are involved in causing the diabetic state. For that reason, the authors studied gland size and expression of adenylyl cyclase isoforms in adrenal glands from Goto-Kakizaki and normal rats. Goto-Kakizaki rat adrenals were found to weigh only about half as much as those of control rats. This decrease was the result of a reduction of the cortex, especially of the zona fasciculata, whereas the medulla was unaffected. Cell density measurements showed that the total number of medullary cells in Goto-Kakizaki rats was lower than that in controls. In the cortex, the cell density did not differ between the two groups; thus, our results point to a marked hypotrophy. In the medulla of Goto-Kakizaki rats, the nuclear size was significantly increased, and there was also an overexpression of adenylyl cyclase 1, 2, 4, 6, and 8 isoforms in the adrenalin-producing cells, indicating an increased functional capacity. In the cortex, despite the cortical hypotrophy, adenylyl cyclase 5 immunoreactivity was markedly increased in Goto-Kakizaki rats, especially in the zona reticularis. It is unclear whether this morphologic change in the diabetic adrenal glands together with the overexpression of different adenylyl cyclase isoforms plays a role in the pathogenesis of this diabetic state or is a genetic defect or compensatory mechanism of diabetes in this spontaneous rodent model of type 2 diabetes.
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PMID:Increased expression of adenylyl cyclase isoforms in the adrenal gland of diabetic Goto-Kakizaki rat. 1260 10

Cyclic 3'5'AMP is an important physiological amplifier of glucose-induced insulin secretion by the pancreatic islet beta-cell, where it is formed by the activity of adenylyl cyclase, especially in response to the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). These hormones are secreted from the small intestine during and following a meal, and are important in producing a full insulin secretory response to nutrient stimuli. Cyclic AMP influences many steps involved in glucose-induced insulin secretion and may be important in regulating pancreatic islet beta-cell differentiation, growth and survival. Cyclic AMP (cAMP) itself is rapidly degraded in the pancreatic islet beta-cell by cyclic nucleotide phosphodiesterase (PDE) enzymes. This review discusses the possibility of targeting cAMP mechanisms in the treatment of type 2 diabetes mellitus, in which insulin release in response to glucose is impaired. This could be achieved by the use of GLP-1 or GIP to elevate cAMP in the pancreatic islet beta-cell. However, these peptides are normally rapidly degraded by dipeptidyl peptidase IV (DPP IV). Thus longer-acting analogues of GLP-1 and GIP, resistant to enzymic degradation, and orally active inhibitors of DPP IV have also been developed, and these agents were found to improve metabolic control in experimentally diabetic animals and in patients with type 2 diabetes. The use of selective inhibitors of type 3 phosphodiesterase (PDE3B), which is probably the important pancreatic islet beta-cell PDE isoform, would require their targeting to the islet beta-cell, because inhibition of PDE3B in adipocytes and hepatocytes would induce insulin resistance.
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PMID:Targeting beta-cell cyclic 3'5' adenosine monophosphate for the development of novel drugs for treating type 2 diabetes mellitus. A review. 1556 54

Cyclic 3'5'-AMP (cAMP) is an important physiological amplifier of glucose-induced insulin secretion by the pancreatic islet beta-cell. In the beta-cell, cAMP is formed by the activity of adenylyl cyclase, especially in response to the incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide. cAMP may also play a similar role in regulating GLP-1 secretion from intestinal L-cells. cAMP influences many steps involved in glucose-induced insulin secretion and may be important in regulating pancreatic islet beta-cell differentiation, growth and survival. cAMP itself is rapidly degraded in the pancreatic islet beta-cell by cyclic nucleotide phosphodiesterase enzymes. This review will discuss the possibility of targeting cAMP mechanisms in the treatment of type 2 diabetes mellitus, in which insulin release in response to glucose is impaired.
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PMID:Modulation of cyclic nucleotides and cyclic nucleotide phosphodiesterases in pancreatic islet beta-cells and intestinal L-cells as targets for treating diabetes mellitus. 1708 34

Erythrocytes of humans have been reported to stimulate nitric oxide (NO) synthesis in the circulation as a consequence of their ability to release ATP in response to both mechanical deformation and exposure to reduced oxygen tension. It has been proposed that the ability of the erythrocyte to affect local vascular resistance permits it to participate in the regulation of blood flow such that oxygen delivery is matched with metabolic need. A signal transduction pathway that relates deformation and exposure to reduced oxygen tension to ATP release from human erythrocytes has been described. The heterotrimeric G protein, Gi, is a critical component of this pathway. Importantly, stimulation of Gi results in activation of adenylyl cyclase and ATP release from these cells. Recently, in a model of diabetes mellitus in rats, expression of Gi was reported to be decreased in the aorta. We report that expression of G alpha 12 is selectively decreased in erythrocytes of humans with type 2 diabetes (DM2) and that these erythrocytes fail to release ATP in response to incubation with mastoparan 7 (10 microM), an agent that activates Gi. These results provide support for the hypothesis that ATP release from erythrocytes of humans with DM2 is impaired and this defect in erythrocyte physiology could contribute to the vascular disease associated with this clinical condition.
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PMID:Expression of the heterotrimeric G protein Gi and ATP release are impaired in erythrocytes of humans with diabetes mellitus. 1708 91

Human erythrocytes, by virtue of their ability to release ATP in response to physiological stimuli, have been proposed to participate in the regulation of local blood flow. A signal transduction pathway that relates these stimuli to ATP release has been described and includes the heterotrimeric G protein G(i) and adenylyl cyclase (AC). In this cell, G(i) activation results in increases in cAMP and, ultimately, ATP release. It has been reported that G(i) expression is decreased in animal models of diabetes and in platelets of humans with type 2 diabetes. Here, we report that G(i2) expression is selectively decreased in erythrocytes of humans with type 2 diabetes and that this defect is associated with reductions in cAMP accumulation and ATP release in response to incubation of erythrocytes with mastoparan 7 (10 micromol/l), an activator of G(i). Importantly, this defect in ATP release correlates inversely with the adequacy of glycemic control as determined by levels of HbA(1c) (A1C). These results demonstrate that in erythrocytes of humans with type 2 diabetes, both G(i) expression and ATP release in response to mastoparan 7 are impaired, which is consistent with the hypothesis that this defect in erythrocyte physiology could contribute to the vascular disease associated with this clinical condition.
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PMID:Reduced expression of G(i) in erythrocytes of humans with type 2 diabetes is associated with impairment of both cAMP generation and ATP release. 1713 May 8

Glucagon-like peptide 1 (GLP-1) is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate, and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past 20 years culminating in a naturally occurring GLP-1 receptor (GLP-1R) agonist, exendin 4 (Ex-4), now being used to treat type 2 diabetes mellitus (T2DM). GLP-1 engages a specific guanine nucleotide-binding protein (G-protein) coupled receptor (GPCR) that is present in tissues other than the pancreas (brain, kidney, lung, heart, and major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1R activation, adenylyl cyclase (AC) is activated and cAMP is generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the protein kinase A (PKA) and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1R activation also increases insulin synthesis, beta cell proliferation, and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in T2DM patients treated with Ex-4. This review will focus on the effects resulting from GLP-1R activation in the pancreas.
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PMID:Mechanisms of action of glucagon-like peptide 1 in the pancreas. 1730 74

TNF-alpha has several effects on adipocytes that may be related to the development of type 2 diabetes in obese subjects. Many studies demonstrated that long-term treatment with TNF-alpha increases lipolysis in adipocytes. However, the short-term (<4 h) effects of TNF-alpha on lipolysis have not been well investigated. The aim of this study was to investigate the short-term regulatory mechanism of TNF-alpha-induced lipolysis in 3T3-L1 adipocytes. Well-differentiated 3T3-L1 adipocytes were used. Lipolysis was determined by measuring glycerol release. Expression of inducible nitric oxide (iNOS) and nitric oxide (NO) production were measured, respectively, by Western blots and the Griess reagent. A selective iNOS inhibitor (s-ethylisothiourea . HBr), an adenylyl cyclase inhibitor (SQ22536), and a guanylyl cyclase inhibitor (LY83583) were used to investigate the involvement of iNOS, cAMP, and cGMP in TNF-alpha-induced lipolysis. Transient transfection with iNOS short hairpin RNA was performed to confirm the involvement of iNOS in TNF-alpha-induced lipolysis. Phosphorylation of hormone-sensitive lipase (HSL) was measured by immunoprecipitation and Western blotting. Results showed that short-term TNF-alpha treatment significantly increased lipolysis, iNOS expression, and NO production in a time- and dose-dependent manner. Furthermore, treatment with the NO donor S-nitroso-N-acetylpenicillamine also stimulated lipolysis and HSL phosphorylation in 3T3-L1 adipocytes. Moreover, pretreatment with inhibitors of iNOS and guanylate cyclase, but not an adenylate cyclase inhibitor, abolished TNF-alpha-induced lipolysis and HSL phosphorylation. Suppression of TNF-alpha-induced iNOS expression using short hairpin RNA significantly reduced TNF-alpha-induced lipolysis. In conclusion, short-term TNF-alpha treatment induces lipolysis in 3T3-L1 adipocytes by increasing iNOS expression and NO production, which activates the guanylyl cyclase/cGMP-dependent pathway and induces phosphorylation of HSL.
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PMID:Short-term regulation of tumor necrosis factor-alpha-induced lipolysis in 3T3-L1 adipocytes is mediated through the inducible nitric oxide synthase/nitric oxide-dependent pathway. 1981 72

Activity of the adenylate cyclase signaling system was evaluated in the testicular tissue of rats with neonatal streptozotocin-induced diabetes (120 and 180 days duration). This state is similar to type 2 diabetes in humans. The regulation of this system by polypeptide hormones and biogenic amines was studied. Sensitivity of the adenylate cyclase signaling system to the regulatory effect of human chorionic gonadotropin and PACAP (pituitary adenylyl cyclase-activating polypeptide) was significantly reduced. The effects of these agents are realized via stimulatory G proteins. Somatostatin, acting through inhibitory G proteins, produced less pronounced effect on the adenylate cyclase signaling system. The increase in the duration of diabetes was accompanied by a decrease in the stimulatory effects of human chorionic gonadotropin and PACAP on adenylate cyclase. Sensitivity of the adenylate cyclase signaling system to biogenic amines remained unchanged (serotonin) or increased under these conditions (epinephrine). Our results indicate that changes in hormonal regulation of the adenylate cyclase signaling system and functional activity of cAMP-dependent signaling cascades are important factors for dysfunction of spermatogenesis and steroidogenesis during insulin-independent diabetes.
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PMID:Changes in hormone sensitivity of the adenylate cyclase signaling system in the testicular tissue of rats with neonatal streptozotocin-induced diabetes. 2039 97

In the 1970s, glucose-dependent insulinotropic polypeptide (GIP, formerly gastric inhibitory polypeptide), a 42-amino acid peptide hormone, was discovered through a search for enterogastrones and subsequently identified as an incretin, or an insulinotropic hormone secreted in response to intraluminal nutrients. Independent of the discovery of GIP, the K-cell was identified in small intestine by characteristic ultrastructural features. Subsequently, it was realized that K-cells are the predominant source of circulating GIP. The density of K-cells may increase under conditions including high-fat diet and obesity, and generally correlates with plasma GIP levels. In addition to GIP, K-cells secrete xenin, a peptide with as of yet poorly understood physiological functions, and GIP is often colocalized with the other incretin hormone glucagon-like peptide-1 (GLP-1). Differential posttranslational processing of proGIP produces 30 and 42 amino acid versions of GIP. Its secretion is elicited by intraluminal nutrients, especially carbohydrate and fat, through the action of SGLT1, GPR40, GPR120, and GPR119. There is also evidence of regulation of GIP secretion via neural pathways and somatostatin. Intracellular signaling mechanisms of GIP secretion are still elusive but include activation of adenylyl cyclase, protein kinase A (PKA), and protein kinase C (PKC). GIP has extrapancreatic actions on adipogenesis, neural progenitor cell proliferation, and bone metabolism. However, the clinical or physiological relevance of these extrapancreatic actions remain to be defined in humans. The application of GIP as a glucose-lowering drug is limited due to reduced efficacy in humans with type 2 diabetes and its potential obesogenic effects demonstrated by rodent studies. There is some evidence to suggest that a reduction in GIP production or action may be a strategy to reduce obesity. The meal-dependent nature of GIP release makes K-cells a potential target for genetically engineered production of satiety factors or glucose-lowering agents, for example, insulin. Transgenic mice engineered to produce insulin from intestinal K-cells are resistant to diabetes induced by a beta-cell toxin. Collectively, K-cells and GIP play important roles in health and disease, and both may be targets for novel therapies.
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PMID:K-cells and glucose-dependent insulinotropic polypeptide in health and disease. 2109 98


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