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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Islet amyloidosis (IA) is the principal lesion in the endocrine pancreas of human beings with non-insulin-dependent diabetes mellitus (NIDDM) and in the similar forms of diabetes mellitus in domestic cats and macaques. As such, the delineation of the pathogenesis of this form of amyloidosis may be crucial to the understanding of the development and progression of NIDDM. Islet amyloid polypeptide (IAPP) is a recently discovered polypeptide that is the principal constituent of IA in human beings, cats, and macaques. IAPP is produced by the pancreatic beta-cells and is co-packaged with insulin in the beta-cell secretory vesicles. Immunohistochemical and physiologic evidence supports the notion that the beta-cells are heterogenous with respect to their relative contents of insulin and IAPP. Therefore, although IAPP is co-secreted with insulin in response to a variety of well-known insulin secretagogues, the molar ratio of these two proteins that is released from the islets may vary, depending upon the glucose concentration and prevailing metabolic milieu. IAPP is highly conserved among mammalian species and has about 45% homology to another neuropeptide, calcitonin gene-related peptide. IAPP is encoded by a single-copy gene located, in the human being, on chromosome 12. IAPP is expressed as a 93 (murine)-89 (human)-amino acid prepropolypeptide that is processed enzymatically, resulting in the removal of amino- and carboxy-terminal propeptide segments. The 20-29 region of the IAPP molecule is most important in the ability of IAPP to form amyloid fibrils. The role of IAPP and IA in the pathogenesis of human NIDDM and similar forms of diabetes mellitus in cats and macaques may involve several possible mechanisms, including 1) direct physical/chemical damage to beta-cells, resulting in necrosis and loss of functional islet tissue, 2) biologic activities of IAPP that oppose those of insulin or abnormally suppress insulin secretion, and 3) interference by IA deposits of passage of insulin out of beta-cells and/or entrance of glucose and other secretogogues into the islet. The roles of each of these possible mechanisms have yet to be demonstrated. In addition, the physiological significance of the apparent IAPP deficiency in both insulin-dependent diabetes mellitus and NIDDM is currently unknown.
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PMID:Islet amyloid polypeptide: a review of its biology and potential roles in the pathogenesis of diabetes mellitus. 821 54

1. Adult male Wistar rats were treated with streptozotocin (65 mg kg-1, i.p.) to induce diabetes. Subgroups of age-matched control and streptozotocin-treated rats were given daily injections of mixed brain bovine gangliosides (60 mg kg-1 body weight, i.p.). At eight weeks after treatment mesenteric arterial beds from rats in each of the four groups were isolated and perfused and the function of perivascular nerves (sympathetic and sensory-motor), endothelium and smooth muscle was assessed. 2. Values for basal tone of mesenteric beds from diabetic and diabetic-ganglioside rats were significantly lower than those of the control and control-ganglioside-treated rats. Perfusion pressures at basal tone were 25.55 +/- 0.8 (n = 11), 22.58 +/- 1.5 (n = 12), 28.42 +/- 1.6 (n = 12) and 30.67 +/- 1.9 (n = 12) mmHg for diabetic, diabetic-ganglioside, control and control-ganglioside-treated rats respectively. 3. There was no difference between the groups with respect to vasoconstrictor responses to sympathetic nerve stimulation, or to doses of noradrenaline. Vasoconstrictor responses to potassium chloride were also similar between the groups. 4. Perivascular nerve stimulation in the presence of the sympathetic blocker guanethidine (3 microM), with tone of the preparation raised with methoxamine (3-100 microM), elicited frequency-dependent vasodilatation of mesenteric arterial beds due to transmitter release from sensory-motor nerves. Sensory-motor nerve-induced vasodilator responses of mesenteric arterial beds from streptozotocin-diabetic and ganglioside-treated diabetic rats were significantly smaller than those of mesenteric beds from the controls (untreated and ganglioside-treated). Vasodilator responses to exogenously applied calcitonin gene-related peptide, the principal vasodilator transmitter released from these nerves, were not different between the groups. Vasodilator responses to the sensory neurotoxin capsaicin were also not different between the groups.5. Endothelium-dependent vasodilator responses to acetylcholine were similar between the groups as were those to the endothelium-independent vasodilator sodium nitroprusside.6. These results indicate that streptozotocin-induced diabetes produces marked impairment of sensory motor nerve function in the rat mesenteric arterial bed. The significantly lower basal perfusion pressures of mesenteric beds from diabetic rats compared to controls may be a reflection of sympathetic dysfunction, but no differences were apparent from the vasoconstrictor responses produced when sympathetic nerves were electrically stimulated. There was no evidence for changes in endothelial vasodilator function, or smooth muscle vasodilator and vasoconstrictor function. Ganglioside treatment did not modify any aspect of vascular function of mesenteric beds from streptozotocin-diabetic or control rats.
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PMID:Impaired sensory-motor nerve function in the isolated mesenteric arterial bed of streptozotocin-diabetic and ganglioside-treated streptozotocin-diabetic rats. 829 99

Anesthetized male Sprague-Dawley rats (350-400 g) were injected intravenously with either 0.1, 1, 15, or 25 nmol rat islet amyloid polypeptide (IAPP), 65 or 650 pmol rat calcitonin gene-related peptide (CGRP), or saline alone. IAPP at the two highest doses decreased the mean arterial blood pressure (BP), increased blood glucose concentrations, and decreased serum insulin concentrations. CGRP at both doses decreased the BP but did not affect the blood glucose concentrations. The blood flow to the whole pancreas, pancreatic islets, adrenal glands, colon, duodenum, liver, and kidney was measured with a microsphere technique 30 min after administration of IAPP and 3 min after injection of CGRP. The two higher doses of IAPP (15 and 25 nmol) markedly reduced the whole pancreatic blood flow, whereas the islet blood flow remained unaffected. This resulted in an increase in the fraction of whole pancreatic blood flow diverted through the islets from approximately 10 to 17%. No blood flow changes in the pancreas or the islets were observed when 0.1 or 1 nmol IAPP was injected. CGRP at both doses caused a decrease in both whole pancreatic and islet blood flow. No changes in fractional islet blood flow were observed, despite similar effects on mean arterial BP as observed after IAPP injections. Neither adrenal, duodenal, colonic, hepatic, skeletal muscle, nor renal blood flow were significantly affected by any of the concentrations of IAPP used, whereas 650 pmol CGRP decreased both duodenal and colonic blood flow. We conclude that IAPP and CGRP have different effects on pancreatic islet blood flow and that IAPP may be of importance for islet blood flow regulation.
Diabetes 1994 Mar
PMID:Pancreatic islet blood flow in the rat after administration of islet amyloid polypeptide or calcitonin gene-related peptide. 831 19

Islet amyloid polypeptide (IAPP or amylin) was first identified as the major peptide constituent of amyloid deposited in the islets of Langerhans in patients with type-2 diabetes mellitus or in insulinomas. It was subsequently shown that IAPP is produced by the pancreatic beta-cells, co-stored and co-released with insulin. IAPP is homologous with the neuropeptide calcitonin gene-related peptide (CGRP) and has therefore been assumed to have a function as an endocrine, paracrine or autocrine hormone. This has prompted the search for its physiological function as well as a putative pathogenic role in type 2 diabetes mellitus.
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PMID:Islet amyloid polypeptide--hen or egg in type 2 diabetes pathogenesis? 832 56

Islet amyloid polypeptide (IAPP) in a 37 amino-acid pancreatic islet polypeptide, displaying about 50% amino-acid homology with neuropeptide calcitonin gene-related peptide (CGRP). IAPP is co-stored with insulin in the beta-cell secretory granules and co-released with insulin upon stimulation. Human IAPP has the ability to precipitate in the shape of amyloid in patients with type II (non-insulin dependent) diabetes but otherwise its functional or pathophysiological role is enigmatic. In the present study 125I-labelled rat IAPP was injected i.v. into female Sprague-Dawley rats and the distribution of the peptide was examined by whole-body autoradiography at intervals from 2 to 30 min after administration. Already after 2 min high radioactivity occurred in the lung parenchyma and in the villi of the small intestinal mucosa. The high radioactivity in these tissues persisted at 10 min but at 30 min the radioactive labelling had decreased to a level only slightly higher than that observed in the blood. A high uptake of radioactivity was also seen in the cortex of the kidney. In other tissues, including the liver, the skeletal muscle, and the exocrine and endocrine pancreas, the radioactivity was low and did not exceed that of the blood. The uptake of 125I-IAPP in the lungs and in the small intestine was inhibited by simultaneous injections of either an excess of unlabelled rat IAPP or unlabelled rat CGRP. This indicates that the labelled structures observed in the lung and the small intestine after injection of 125I-IAPP alone was due to binding to receptors for IAPP or CGRP in these tissues. The accumulation of radioactivity in the kidneys was not affected by pretreatment with high doses of unlabelled IAPP or CGRP. This unspecific uptake of radioactivity may be due to reabsorption of labelled IAPP in the proximal tubuli. Our results indicate the presence of receptors binding IAPP in the lung parenchyma and in the villi of the small intestinal mucosa. This, in turn, may imply prominent biological activities of IAPP at these sites.
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PMID:Whole-body autoradiography of 123I-labelled islet amyloid polypeptide (IAPP). Accumulation in the lung parenchyma and in the villi of the intestinal mucosa in rats. 832 57

Glucagon and the glucagon receptor are a primary source of control over blood glucose concentrations and are especially important to studies of diabetes in which the loss of control over blood glucose concentrations clinically defines the disease. A complementary DNA clone for the glucagon receptor was isolated by an expression cloning strategy, and the receptor protein was expressed in several kidney cell lines. The cloned receptor bound glucagon and caused an increase in the intracellular concentration of adenosine 3', 5'-monophosphate (cAMP). The cloned glucagon receptor also transduced a signal that led to an increased concentration of intracellular calcium. The glucagon receptor is similar to the calcitonin and parathyroid hormone receptors. It can transduce signals leading to the accumulation of two different second messengers, cAMP and calcium.
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PMID:Expression cloning and signaling properties of the rat glucagon receptor. 838 75

Data are presented concerning the basal levels of parathormone and calcitonin and the effect of dihydropyridine derivatives on the characteristics of haemodynamics as well as pancreatic secretory activity in patients with diabetes mellitus. It is shown that in diabetic patients with hypertension a single administration of the drugs induces vasodilatation which causes lowering of systolic and diastolic blood pressure. In patients with diabetes mellitus in combination with hypertension, heart coronary disease and obvious peripheral angiopathy (similar procedure) no peripheral vasodilatation was observed. No negative effects were observed on the compensatory processes (and obviously on pancreatic secretory activity in patients with both insulin-dependent and insulin-independent diabetes mellitus even during long-lasting administration of drugs. A conclusion is made that calcium channel antagonists should be recommended to patients with diabetes mellitus taking into account the state of their peripheral vessels.
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PMID:[Effect of calcium antagonists on the hemodynamic and pancreatic secretory parameters in diabetes mellitus]. 840 42

Diabetic neuropathy affects both sensory and autonomic peripheral nerve fibres. Vasoactive intestinal polypeptide (VIP) is present in autonomic fibres which modulate sweat secretion, while calcitonin gene-related peptide (CGRP) is localized to cutaneous sensory fibres. In this study, immunohistochemistry and image analysis were used to assess changes of VIP and CGRP, and of the pan-neuronal marker protein gene-product (PGP)-9.5, in skin biopsies of 18 patients affected by type 1 diabetes (age range 18-46 years) and from seven aged-matched controls. Patients were divided into three groups: group 1 (n = 6), with diabetes for 6 months to 3 years; group 2 (n = 5), with the disease for 5-10 years; and group 3 (n = 7), with diabetes for more than 10 years. VIP immunoreactivity (IR) and PGP-9.5-IR were significantly reduced around sweat glands (P < 0.005) in groups 2 and 3. Epidermal CGRP-IR and PGP-9.5-IR were significantly reduced in group 3 (P < 0.05). Twenty-eight per cent (5/18) of all patients showed high VIP-IR around sweat glands (> 95 per cent confidence limits of controls) and all of these patients had diabetes for less than 3 years. Conversely, 55 per cent (10/18) of patients had low VIP-IR (< 5 per cent confidence limit of controls). The latter, compared with the former, showed a significantly longer duration of diabetes (Fisher exact test P = 0.002), presence of clinical autonomic neuropathy (Fisher exact test P = 0.04), and a reduced sural nerve conduction velocity (Fisher exact test P = 0.04). These results suggest that quantitative immunohistochemical analysis of peptide-containing cutaneous nerves allows an objective evaluation of nerve fibre alterations at early stages of diabetes than is currently possible with neurophysiological functional tests.
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PMID:Early increase precedes a depletion of VIP and PGP-9.5 in the skin of insulin-dependent diabetics--correlation between quantitative immunohistochemistry and clinical assessment of peripheral neuropathy. 844 92

Amylin is a recently discovered 37 amino acid peptide secreted into the bloodstream, along with insulin, from pancreatic beta-cells. It is about 50% identical to calcitonin gene-related peptides (CGRP alpha and CGRP beta) and structurally related to the calcitonins. Amylin can elicit the vasodilator effects of CGRP and the hypocalcaemic actions of calcitonin, while these peptides can mimic newly discovered actions of amylin on carbohydrate metabolism. The different relative potencies of these peptides suggest that they act with different selectivities at a family of receptors. Amylin is deficient in insulin-dependent diabetes mellitus, while plasma levels are elevated in insulin-resistant conditions such as obesity and impaired glucose tolerance. In this Viewpoint article, Tim Rink and colleagues propose that amylin is an endocrine partner to insulin and glucagon; deficiency or excess of amylin may therefore contribute to important metabolic diseases.
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PMID:Structure and biology of amylin. 851 54

The perivascular innervation of the superior mesenteric artery and vein was examined using immunohistochemical and immunoassay techniques in rats 8 weeks after induction of diabetes with streptozotocin (STZ). Increased density of innervation and fluorescence intensity was noted for substance P- and calcitonin gene-related peptide-immunoreactive nerves in the diabetic vessels. A slight increase in the density of vasoactive intestinal polypeptide-immunoreactive nerve fibers innervating the mesenteric artery was also noted. However, there was no change in the density of neuropeptide Y- and dopamine beta-hydroxylase-immunoreactive nerve fibers, although the fluorescence intensity of neuropeptide Y-immunoreactive nerve fibers was reduced in diabetic rat vessels. Immunoassays showed that the levels of substance P- and calcitonin gene-related peptide were increased > 10-fold in the diabetic mesenteric vein, while levels of neuropeptide Y and vasoactive intestinal polypeptide were unchanged. In summary, there is a marked increase in nerve fibers containing sensory neuropeptides in mesenteric vessels of STZ-induced diabetic rats, which, in view of the reported impaired sensorimotor function in these vessels, is likely to reflect a neuropathic change.
Diabetes 1996 Feb
PMID:Selective damage to sensorimotor perivascular nerves in the mesenteric vessels of diabetic rats. 854 56


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