Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Regulation of pulsatile secretion of growth hormone (GH) relies on hypothalamic neuronal loops, major transmitters involved in their operation are growth hormone releasing hormone (GHRH) synthetized mostly in arcuate nucleus (ARC) neurons, and somatostatin (SRIH), synthetized both in hypothalamus periventricular (PVe) and ARC neurons. 2. Neurons synthetizing both peptides can inhibit each other in a reciprocal manner. Other neuropeptides synthetized in ARC neurons, such as galanin, or in ARC interneurons, such as neuropeptide Y (NPY), are able to modulate synthesis and release of GHRH and SRIH into the hypothalamohypophyseal portal system. 3. In addition, the hitherto uncharacterized endogenous ligand of the recently cloned growth hormone releasing peptide receptor, expressed mostly in the ARC, triggers GH release, presumably by actions on ARC interneurons. 4. Thyroid, gonadal, and adrenal steroid hormones also affect the GHRH-SRIH balance; a differential distribution of sex steroid receptors in the ARC and the PVe is likely to account for the different pattern of GH secretion in male and female animals. 5. Growth hormone itself is able to inhibit the amplitude of GH secretory episodes and to increase their frequency, by entering the brain (presumably by receptor-mediated internalization at the level of the choroid plexus) and acting subsequently on ARC neurons. 6. At the pituitary level, major neurotransmitters regulating GH cells act on receptors of the VIP/PACAP/GHRH family and of the somatostatin family, in particular, sst2 and sst3. Those are coupled to accumulation of cAMP as a second messenger. 7. In addition, patch-clamp experiments and measurement of intracellular Ca2+ indicate that GH cells present characteristic, GHRH-dependent, but self-maintained Ca2+ spikes and [Ca2+]i transients, which reflect adaptive mechanisms to constraints of episodic release. 8. Recent data on transcription factors affecting GH gene expression and somatotrope differentiation are also summarized. 9. Regulation and differentiation of somatotropes also depend upon paracrine processes within the pituitary itself and involve growth factors and several neuropeptides, for instance, vasoactive intestinal peptide, angiotensin 2, endothelin, and activin. 10. Finally, characteristic changes occur in the GH secretory pattern under discrete, pathological conditions, such as abnormal growth and dwarfism, diabetes, and acromegaly, as well as during inflammatory processes.
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PMID:Hypothalamic and hypophyseal regulation of growth hormone secretion. 952 32

Insulin secretion by isolated islets of Langerhans from 19 human donors (9 women and 10 men) was studied in vitro to test the hypothesis that human islets contain both the K(ATP) channel-dependent and the K(ATP) channel-independent signaling pathways. The results demonstrated the presence of both of these major pathways of glucose signaling. Thus, insulin secretion was stimulated by high glucose concentrations, by the sulfonylurea tolbutamide, and by a depolarizing concentration of potassium chloride. Diazoxide, which activates the K(ATP) channel, completely blocked the stimulation of release by glucose. Stimulation of insulin release by tolbutamide, which inhibits the K(ATP) channel and depolarizes the beta-cell, and inhibition of glucose-stimulated release by diazoxide, which activates the channel and repolarizes the beta-cell, confirm the involvement of the K(ATP) channel-dependent pathway in glucose signaling. The participation of the K(ATP) channel-independent pathway in the stimulation of insulin release by glucose was demonstrated for the first time in human islets. This was done in two ways. The first method, in the presence of diazoxide, blocked the action of glucose on the K(ATP) channel in combination with a depolarizing concentration of KCl to raise [Ca2+]i. Under these conditions, glucose stimulated insulin release. A second method to demonstrate the involvement of the K(ATP) channel-independent pathway was to close the K(ATP) channels with tolbutamide. Again, with no possibility of further action on the K(ATP) channel, glucose stimulated insulin release. In a final series of experiments, glucose-stimulated insulin release was profoundly inhibited by somatostatin, clonidine, and prostaglandin E2, but not by galanin.
Diabetes 1998 May
PMID:Glucose activates both K(ATP) channel-dependent and K(ATP) channel-independent signaling pathways in human islets. 958 47

Twelve pre-diabetic and 12 diabetic female NOD mice aged 22-24 weeks were studied. As controls, 12 female BALB/cJ of the same age and sex were used. The duodenal content of several neuropeptides, namely vasoactive intestinal polypeptide (VIP), neurotensin, neuropeptide Y (NPY), galanin, gastrin-releasing peptide (GRP) and enkephalin was determined by radioimmunoassay of tissue extracts. The VIP content in duodenal extracts from both pre-diabetic and diabetic NOD mice was significantly higher than that of the controls. The enkephalin content of the duodenum of diabetic mice was significantly higher than that of the controls, while no significant difference was found between the controls and pre-diabetic mice. There was no statistically significant difference between controls and NOD mice regarding the duodenal content of neurotensin, NPY, galanin or GRP. It has been suggested that the high duodenal content of VIP appears to be primary to the onset of diabetes and that the high enkephalin content may be attributable to the diabetic state. The changes in the duodenal content of VIP and enkephalin reported here in an animal model for diabetes type I might be of relevance for the gastrointestinal complications occurring in human diabetes.
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PMID:Neuropeptide contents in the duodenum of non-obese diabetic mice. 962 83

The role of the cholinergic and peptidergic pathways in the impairment of gastric motility associated with diabetic gastroparesis was assessed at the postsynaptic level using isolated fundus smooth muscle strips. Maximal contractile responses to carbachol and galanin were significantly decreased in fundus strips isolated from rats rendered diabetic by a single intraperitoneal injection of streptozotocin (STZ, 70 mg/kg) 1, 4 and 8 weeks before experiments. We also observed notable decrements in the slopes and Hill's coefficients without conspicuous changes in the EC50 of the respective galanin concentration-response curves measured in strips obtained from STZ animals after 4 and 8 weeks. L-NAME reversed the above-mentioned alterations in an L-arginine-sensitive manner in STZ rats after 4 weeks but not in STZ rats after 8 weeks. The blood plasma nitrite/nitrate levels in STZ animals after 4 and 8 weeks were increased by 44.6 and 61.9%, respectively. Ca2+-independent nitric oxide synthase activity in gastric fundus strips and stomach corpus mucosa from STZ rats after 4 weeks was markedly enhanced by 37.4 and 31.9%, respectively, suggesting an enhanced nitric oxide production. In vivo insulin treatment prevented diabetes-induced alterations in smooth muscle contractility. We conclude that the smooth muscle dysfunction evoked by experimental diabetes causing diminished contractions of fundus strips to carbachol and galanin is at least partly due to the increased nitric oxide synthesis.
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PMID:Effects of diabetes mellitus on the contractile activity of carbachol and galanin in isolated gastric fundus strips of rats. 969 Dec 26

A definitive assessment of the relative roles of insulin resistance and insulin deficiency in the etiology of NIDDM is hampered by several problems. 1) Due to better methodology, data on insulin resistance are generally more accurate and consistent than data on insulin deficiency. 2) In source data, case-control studies are prone to selection bias, while epidemiological associations, whether cross-sectional or longitudinal, are liable to misinterpretation. 3) Insulin secretion and action are physiologically interconnected at multiple levels, so that an initial defect in either is likely to lead with time to a deficit in the companion function. The fact that both insulin resistance and impaired insulin release have been found to precede and predict NIDDM in prospective studies may be in part a reflection of just such relatedness. 4) Direct genetic analysis is effective in rarer forms of glucose intolerance (MODY, mitochondrial mutations, etc.) but encounters serious difficulties with typical late-onset NIDDM. Despite these uncertainties, the weight of current evidence supports the view that insulin resistance is very important in the etiology of typical NIDDM for the following reasons: 1) it is found in the majority of patients with the manifest disease; 2) it is only partially reversible by any form of treatment (117); 3) it can be traced back through earlier stages of IGT and high-risk conditions; and 4) it predicts subsequent development of the disease with remarkable consistency in both prediabetic and normoglycemic states. Of conceptual importance is also the fact that the key cellular mechanisms of skeletal muscle insulin resistance (defective stimulation of glucose transport, phosphorylation, and storage into glycogen) have been confirmed in NIDDM subjects by a variety of in vivo techniques [ranging from catheter balance (118) to multiple tracer kinetics (119) to 13C nuclear magnetic resonance spectroscopy (120)], and have been detected also in normoglycemic NIDDM offspring (121). If insulin resistance is a characteristic finding in many cases of NIDDM, insulin-sensitive NIDDM does exist. On the other hand, given the tight homeostatic control of plasma glucose levels in humans, beta-cell dysfunction, relative or absolute, is a sine qua non for the development of diabetes. If insulin deficiency must be present whereas insulin resistance may be present, is this proof that the former is etiologically primary to the latter? If so, do we have convincing evidence that the primacy of insulin deficiency is genetic in nature? The answer to both questions is negative on several accounts. The defect in insulin secretion in overt NIDDM is functionally severe but anatomically modest: beta-cell mass is reduced by 20-40% in patients with long-standing NIDDM (122). Moreover, the insulin secretory deficit is progressively worse with more severe hyperglycemia (123) and recovers considerably upon improving glycemic control (124). These observations indicate that part of the insulin deficiency is acquired (through glucose toxicity, lipotoxicity, or both). In addition, although insulin deficiency is necessary for diabetes, it may not always be sufficient to cause NIDDM. In fact, subtle defects in the beta-cell response to glucose may be widespread in the population (108, 125) and only cause frank hyperglycemia when obesity/insulin resistance stress the secretory machinery. Conceivably, there could be beta-cell dysfunction without NIDDM just as there is insulin resistance without diabetes. Incidentally, any defect in insulin secretion, whether in normoglycemic or hyperglycemic persons, could be due to other factors than primary beta-cell dysfunction: amyloid deposits in the pancreas (126), changes in insulin secretagogues (amylin, GLP-1, GIP, galanin) (127-130), early intrauterine malnutrition (131). Finally, the predictive power of early changes in insulin secretion for the development of typical NIDDM is generally lower than that of insulin
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PMID:Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. 971 76

Perinatal overfeeding is a risk factor for overweight and diabetes during life. Underlying pathophysiological mechanisms are unclear. The peptide galanin is suggested to stimulate food intake by acting within the paraventricular hypothalamic nucleus (PVN). In early postnatally overfed rats overweight and hyperinsulinemia were observed, accompanied by an increased number of galanin-positive neurons in the PVN at weaning. Our results might indicate malformation of hypothalamic galaninergic neurons due to neonatal overfeeding and hyperinsulinism, respectively, in rats.
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PMID:Increased number of galanin-neurons in the paraventricular hypothalamic nucleus of neonatally overfed weanling rats. 991 50

Twelve prediabetic and 12 diabetic non-obese diabetic (NOD) mice, all females aged 22-24 weeks, were investigated. As controls, 12 BLAB/cJ Bom mice of the same age and gender as the NOD mice were used. The concentration of several neuroendocrine peptides was determined by radioimmunoassay of tissue extracts of transmural specimens of antrum and distal colon. The neuroendocrine peptides investigated were peptide YY (PYY), somatostatin, vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), neurotensin, and galanin. In the antrum, VIP, NPY, and galanin concentrations were all significantly lower in prediabetic and diabetic NOD mice than in controls. There was no statistical difference between NOD mice and controls regarding neurotensin content. In the colon, the concentrations of PYY, somatostatin, VIP, NPY, and galanin were lower in prediabetic and diabetic NOD mice than in controls. The concentration of neurotensin in prediabetic, but not in diabetic NOD mice was lower than that of controls. The present observations support the previously reported studies on animal models for human type I diabetes that the neuroendocrine system of the gut is disturbed. It also shows that the neuroendocrine system of the stomach and large intestine is affected. The present findings may have some implications for the gastrointestinal dysfunction observed in patients with human type I diabetes.
J Diabetes Complications
PMID:Neuroendocrine peptides in stomach and colon of an animal model for human diabetes type I. 1050 78

The pancreatic islets are richly innervated by parasympathetic, sympathetic and sensory nerves. Several different neurotransmitters are stored within the terminals of these nerves, both the classical neurotransmitters, acetylcholine and noradrenaline, and several neuropeptides. The neuropeptides, vasoactive intestinal polypeptide, pituitary adenlyate cyclase activating polypeptide and gastrin releasing peptide are constituents of the parasympathetic nerves, whereas the neuropeptides galanin and neuropeptide Y are localised to sympathetic nerve terminals. Furthermore, the neuropeptide calcitonin gene-related peptide is localised to sensory nerves and cholecystokinin is also an islet neuropeptide, although the nature of the cholecystokinin nerves is not established. Stimulation of the autonomic nerves and treatment with neurotransmitters affect islet hormone secretion. Thus, insulin secretion is stimulated by parasympathetic nerves or their neurotransmitters and inhibited by sympathetic nerves or their neurotransmitters. The islet autonomic nerves seem to be of physiological importance in mediating the cephalic phase of insulin secretion, in synchronising the islets to function as a unit allowing oscillations of islet hormone secretion, and in optimising islet hormone secretion during metabolic stress, e.g. hypoglycaemia and neuroglycopenia. The autonomic nerves could also be involved in the islet adaptation to insulin resistance with possible implication for the development of glucose intolerance and Type II (non-insulin-dependent) diabetes mellitus. It is concluded that islet innervation, through the contribution of all branches of the autonomic nerves and several different neurotransmitters is of importance both for the physiology and pathophysiology of the islets.
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PMID:Autonomic regulation of islet hormone secretion--implications for health and disease. 1081 32

Gastrointestinal symptoms in diabetic patients are commonplace, and are believed to be due, at least partly, to neuropathy of the gut. In the present study, therefore, some important neurotransmitters in the myenteric plexus were investigated in non-obese diabetic mice, an animal model of human type 1 diabetes. For this purpose, immunocytochemistry was applied on sections from antrum, duodenum and colon, subsequently quantified by computerized image analysis. Whereas the number of vasoactive intestinal peptide (VIP)-positive neurons was increased in antral myenteric ganglia of diabetic mice, there was a decreased density of nerve fibres in muscularis propria. No difference was seen in the VIP of duodenum and colon. Acetylcholine-containing nerve fibres showed an increased volume density in muscularis propria of antrum and duodenum, but a decreased density in colon of diabetic mice, as compared with controls. There was a decreased number of neurons containing nitric oxide synthase (NOS) in myenteric ganglia of antrum and duodenum. No difference was seen in density of NOS-containing nerve fibres in muscularis propria. There was no difference regarding neuropeptide Y (NPY) and galanin between diabetic and control mice; nor was there any difference between pre-diabetic NOD mice and controls regarding all bioactive substances investigated. It is concluded that the diabetic state affects the innervation of gut in this animal model. The present findings may be of some relevance to the gastrointestinal symptoms seen in patients with diabetes.
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PMID:Diabetic state affects the innervation of gut in an animal model of human type 1 diabetes. 1096 18

Previous studies have identified a susceptibility region for insulin-dependent (type 1) diabetes mellitus on chromosome 11q13 (IDDM4). In this study, 15 polymorphic markers were analyzed for 382 affected sibpair (ASP) families with type 1 diabetes. Our analyses provided additional evidence for linkage for IDDM4 (a peak LOD score of 3.4 at D11S913). The markers with strong linkage evidence are located within an interval of approximately 6 cM between D11S4205 and GALN. We also identified polymorphisms in two candidate genes, Fas-associated death domain protein (FADD) and galanin (GALN). Analyses of the data by transmission/disequilibrium test (TDT) and extended TDT (ETDT) did not provide any evidence for association/linkage with these candidate genes. However, ETDT did reveal significant association/linkage with the marker D11S987 (P=0.0004) within the IDDM4 interval defined by ASP analyses, suggesting that IDDM4 may be in the close proximity of D11S987.
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PMID:Fine-mapping of the type 1 diabetes locus (IDDM4) on chromosome 11q and evaluation of two candidate genes (FADD and GALN) by affected sibpair and linkage-disequilibrium analyses. 1098 76


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