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

With human islets isolated for transplantation, we examined the applicability to humans of a metabolic fuel hypothesis of glucose transduction and a Ca2+ hypothesis of depolarization-secretion coupling, both previously proposed for rodent islet beta-cells. We report that several features of human beta-cell physiology are well accounted for by these hypotheses. With whole-islet perifusion, we demonstrated that insulin secretion induced by glucose, tolbutamide, or elevated K+ is dependent on extracellular Ca2+. Insulin release induced by these secretagogues is enhanced by the dihydropyridine Ca2+ channel agonist BAYk8644 and depressed by the dihydropyridine Ca(2+)-channel antagonist nifedipine. All of the aforementioned secretagogues provoke increases in cytosolic free Ca2+, which are dependent on extracellular Ca2+ and are altered by the dihydropyridine drugs. Individual beta-cells in the islet display diminished resting membrane conductance, graded depolarization, and complex electrical patterns, including bursts of action potentials in response to stimulatory concentrations of glucose or tolbutamide. Individual islet beta-cells display voltage-dependent Ca2+ currents that are activated at membrane potentials traversed during the excursion of the action potential. In most cells, the Ca2+ currents are enhanced by BAYk8644 and depressed by nifedipine at concentrations that have parallel effects on secretagogue-induced increases in cytosolic Ca2+ and insulin secretion. These survey studies should provide the basis for more detailed investigations of the relationship of voltage-dependent ionic currents to electrical activity patterns and of electrical activity patterns to granule exocytosis in single human beta-cells.
Diabetes 1992 Jun
PMID:Stimulus-secretion coupling in beta-cells of transplantable human islets of Langerhans. Evidence for a critical role for Ca2+ entry. 137 75

Felodipine is a vascular-selective, dihydropyridine calcium antagonist previously investigated as a conventional tablet formulation administered twice daily. More recently considerable experience has been gained with an extended release (ER) formulation which has the convenience of once daily administration. Felodipine ER has been well studied in patients with essential hypertension. As monotherapy in mild to moderate essential hypertension, felodipine ER is at least as effective in reducing blood pressure as other calcium antagonists, beta-blockers, diuretics and ACE inhibitors, with some results favouring felodipine ER at a statistically significant level at the dosages used. It is also effective combined with controlled release metoprolol or enalapril in patients with mild to moderate essential hypertension. In patients with more severe forms of essential hypertension uncontrolled by beta-blocker and/or diuretic therapy, felodipine ER was effective as an 'add-on' therapy in placebo-controlled trials, and, at the dosages used, more effective than either sustained release nifedipine or nitrendipine. Felodipine produces effective control of blood pressure without negative effects on cardiac performance. In addition to its antihypertensive action, results suggest that felodipine therapy is associated with significant regression of left ventricular hypertrophy. Furthermore, it appears suitable for use in patients with concomitant diabetes, renal dysfunction or asthma, and is also being investigated for use in patients with congestive heart failure or angina pectoris. Felodipine ER is an effective drug for the treatment of all grades of essential hypertension, and can be used both as monotherapy and in combination with other antihypertensive agents. Further clinical experience should fully establish the long term tolerability of felodipine ER and consequently its place in therapy relative to other accepted antihypertensive drugs. However, with the convenience of once daily administration, felodipine ER is a worthwhile innovation in the treatment of hypertension.
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PMID:Felodipine. A review of the pharmacology and therapeutic use of the extended release formulation in cardiovascular disorders. 138 18

Non-obese diabetic (NOD) mice injected with CD3 antibody as newborns have a reduced incidence of diabetes, raising the possibility that the neonatal injection caused a long-lasting change in circulating T cells. The present study shows that NOD and BALB/c mice injected with soluble CD3 antibody in the first 2 days of life sustained an 80-95% reduction in the number of circulating T cells lasting for 2-3 weeks, with T cells returning after 4 weeks, and reaching control values after 6 weeks. The T cells which appeared in intact mice 4-6 weeks after injection showed no excess of T-cell receptor (TcR) delta expressing cells. They had a similar distribution into CD4 and CD8 subsets as uninjected controls, and a similar usage and cell surface expression of four T-cell receptor V beta families. Labelled CD3 antibody was detected in the serum for up to 2 weeks after injection into neonates and was enriched in the thymus. Adoptively transferred T cells continued to be cleared from the circulation for 4 weeks following antibody injection. The properties of T cells which had been exposed to CD3 neonatally were investigated in animals who were first injected with CD3 antibody and then thymectomized. These animals had reduced numbers of T cells at 12 weeks of age. The surviving T cells showed a Ca2+ flux when stimulated but their proliferation in response to concanavalin A (Con A) was reduced, even in the presence of irradiated accessory cells or T-cell supernatant co-stimulator factors. Although the representation of four different V beta families was the same as in the uninjected controls, the density of expression of the T-cell receptor was reduced. The data indicate that the limited number of T cells which survive the injection are functionally deficient and that an intact thymus is required for full T-cell repopulation following neonatal CD3 injection into NOD mice.
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PMID:T-cell repopulation following neonatal injection of non-obese diabetic (NOD) mice with anti-T-cell antibodies. 138 96

We have investigated the cellular basis for the clinical and epidemiologic linkage of hypertension, left ventricular hypertrophy (LVH), obesity, and non-insulin-dependent diabetes mellitus (NIDDM) and have studied cytosolic free calcium and free magnesium levels in these syndromes. Specifically, intracellular free calcium is elevated and free magnesium is deficient in hypertension, and both are related (directly and inversely, respectively) to the ambient level of blood pressure, to LV mass index (and thus to the degree of cardiac hypertrophy), and to the hyperinsulinemia and insulin resistance of essential hypertension. Dynamically, the ability of dietary salt loading to elevate blood pressure corresponds to its ability to elevate cytosolic free calcium and reciprocally to suppress free magnesium levels. Conversely, the ability of calcium channel blockade to reverse salt-induced hypertension is related to its ability to prevent these transmembrane ionic effects. Higher steady-state free calcium or lower free magnesium, or both, are also observed in clinical states linked to hypertension, such as obesity and NIDDM. Oral glucose loading in normal subjects itself elevates free calcium and suppresses free magnesium levels, as does hyperglycemia in vitro. These data suggest an ionic hypothesis of cardiovascular and metabolic disease, in which a generalized defect in cell ion handling is present in all tissues, resulting in higher steady-state free calcium and lower free magnesium levels. In pancreatic beta cells, this would produce hyperinsulinemia; in fat and skeletal muscle, cause peripheral insulin resistance; and in renal tissue, increase proximal sodium resorption and increase urinary calcium excretion--all features of essential hypertension. In vascular smooth muscle, high cytosolic free calcium would increase smooth muscle tone and cause vasoconstriction, and in heart muscle, independent of blood pressure, would increase contractility and predispose to LVH. Therefore, what may appear clinically to be the separate syndromes of hypertension, obesity, and NIDDM may pathophysiologically be different manifestations of the same underlying cellular defect, thus explaining their frequent clinical coexistence. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion-specific agents, such as calcium channel blocking drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent excess morbidity and mortality of the concurrent cardiac, vascular, and metabolic aspects of the hypertensive state.
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PMID:Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders. 138 62

T cell activation is dependent upon calcium influx and protein kinase C activation, with subsequent lymphocyte proliferation dependent upon IL-2. Abnormalities in T cell proliferation, including abnormal calcium influx and defective protein kinase C activation, have been identified in aged mice and humans and many autoimmune diseases including diabetes, lupus and scleroderma. Since UCD line 200 chickens, which spontaneously develop a scleroderma-like disease, have both thymic defects and a diminished peripheral blood lymphocyte response to IL-2, we have further investigated T cell function in these birds. Interestingly, line 200 T cells respond poorly in vitro to a variety of diversely acting T cell mitogens including concanavalin A, phytohemagglutinin and anti-chicken CD3 monoclonal antibody. Moreover, they do not respond well even to phorbol myristate acetate in conjunction with ionomycin. Addition of exogenous IL-2-containing supernatant concurrently with mitogenic stimulation also had no significant effect. Analysis of intracellular free calcium demonstrated that the lymphocytes from diseased birds had a reduced influx of calcium (or release for intracellular stores) following stimulation. These data clearly reflect a unique defect in T cell activation associated with avian scleroderma. Analysis of chicken CD3, CD4 and CD8 expression revealed a 39% decrease in peripheral blood CD4+ cells in scleroderma birds, although this decrease was not sufficient to explain the 80-90% decrease observed in proliferation assays and calcium influx. Our data support the hypothesis that avian scleroderma is mediated via abnormal function of lymphocyte co-stimulatory molecules or intracellular calcium regulators.
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PMID:Avian scleroderma: evidence for qualitative and quantitative T cell defects. 138 34

Felodipine is a dihydropyridine calcium antagonist which may be administered once daily in an extended release (ER) formulation. As monotherapy in older patients with mild to moderate essential hypertension, felodipine ER once daily provides effective control of blood pressure (BP). The drug has also been effective, either as monotherapy or in combination with other antihypertensive medications, in comparisons with other antihypertensive agents, and does not adversely affect lipid profiles or, in patients with diabetes mellitus, glycaemic control. Results in patients with angina pectoris and congestive heart failure indicate a potential role for felodipine ER in these indications and data also suggest the drug reduces left ventricular hypertrophy. In addition, felodipine ER appears suitable for use in patients with concomitant respiratory disease, renal or hepatic dysfunction, cerebrovascular or peripheral ischaemic disease, or gout, making it particularly useful in the elderly who often have more than one significant clinical condition. Felodipine ER has generally been well tolerated by older patients in clinical trials, although further confirmation in the long term is desirable. Thus, felodipine ER effectively lowers BP in older patients with essential hypertension with the added convenience of once daily administration. It may be used as monotherapy or in combination with other antihypertensive agents and is a practical advance in the treatment of hypertension in the elderly.
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PMID:Felodipine. A review of the pharmacology and therapeutic use of the extended release formulation in older patients. 139 20

1. It has been suggested that hypertension may be an important determinant of the rate of progression of diabetic microangiopathy. 2. Renal microvascular disease as assessed by urinary albumin excretion and glomerular ultrastructure was evaluated in a model in which streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR). 3. Diabetes was associated with increases in urinary albumin excretion, and hypertension resulted in a further increase in albuminuria. 4. Various antihypertensive regimens were administered to diabetic SHR, with the angiotensin-converting enzyme inhibitor perindopril and triple therapy (hydralazine, reserpine and hydrochlorothiazide) being more effective than the calcium antagonist (lacidipine) in retarding the increase in albuminuria in diabetic SHR. 5. Antihypertensive therapy appears to ameliorate the development of diabetic renal disease.
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PMID:Diabetic renal microvascular disease: the role of hypertension and ACE inhibitors. 139 13

Herein, we review the applicability to human beta-cells of an electrophysiologically based hypothesis of the coupling of glucose metabolism to insulin secretion. According to this hypothesis, glucose metabolism leads to the generation of intracellular intermediates (including ATP), which leads to closure of ATP-sensitive K+ channels. Channel closure results in membrane depolarization, the onset of electrical activity, and voltage-dependent Ca2+ entry. The resultant rise in cytosolic Ca2+ leads to Ca(2+)-dependent exocytosis of insulin granules. We found that most of the published experimental evidence for human beta-cells supports this hypothesis. In addition, we present three other emerging lines of evidence in support of this hypothesis for human islet beta-cells: 1) the effects of pHi-altering maneuvers on insulin secretion and electrical activity; 2) preliminary identification of LVA and HVA single Ca2+ channel currents; and 3) validation of the feasibility of Cm measurements to track insulin granule exocytosis. On the basis of this last new line of evidence, we suggest that combinations of Cm measurements and electrical activity/membrane current measurements may help define the roles of diverse electrical activity patterns, displayed by human beta-cells, in stimulus-induced insulin secretion.
Diabetes 1992 Oct
PMID:Electrophysiology of stimulus-secretion coupling in human beta-cells. 139 96

Renal osteodystrophy presents with a spectrum of histologic abnormalities. A new entity characterized by a marked decrease in bone turnover without osteoid accumulation, that is, adynamic bone disease, has recently emerged. This new form was thought to be primarily related to aluminum accumulation. Since aluminum-containing phosphate binders have been widely replaced by calcium salts, adynamic bone disease would be expected to disappear over time. However, not only is adynamic bone disease observed in the absence of aluminum intoxication, its incidence does not seem to have decreased. We conducted a retrospective study in 1,803 patients on chronic maintenance dialysis who were biopsied during the last 10 years and assessed the incidence of adynamic bone disease over time in an effort to elucidate the factors associated with its occurrence. Adynamic bone disease was first seen in 1984 in the laboratory. Its incidence increased gradually over the years and, in 1991, still affected approximately 20% of the patients. The primary factors associated with the occurrence of adynamic bone disease include: (a) aluminum accumulation which is currently found in 60% of the patients on chronic maintenance dialysis undergoing biopsies, (b) increasing age of the patients on dialysis, (c) diabetes, and, possibly, (d) chronic ambulatory peritoneal dialysis. The clinical relevance of adynamic bone disease deserves further study. At present, this entity is associated with a tendency towards hypercalcemia, aging of bone due to stunted bone remodeling, a condition which might be associated with impaired repair of physiologic microdamages, and accumulation of microfractures leading to mechanical incompetence and ultimately to higher risk of fractures.
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PMID:Risk of adynamic bone disease in dialyzed patients. 140 83

Amylin, also called islet amyloid polypeptide (IAPP), or diabetes-associated peptide (DAP) is a recently discovered 37 amino acid polypeptide which has been shown to be co-secreted with insulin from the pancreatic beta-cell. The peptide turned out to be the major constituent of pancreatic amyloid deposits which are frequently found in the pancreas of type II diabetic patients. Therefore, a role for amylin in the aetiology of type II diabetes was hypothesized. To investigate this possibility, several studies have been performed to elucidate whether amylin is able to impair insulin secretion and action, two characteristic features of type II diabetes mellitus. These studies suggest that it is unlikely that amylin has a direct inhibitory effect on insulin secretion. Amyloid deposits, however, which are derived from the in situ polymerization and precipitation of amylin, may impair beta-cell function during type II diabetes by damaging and covering beta-cells. Furthermore, it has been shown that amylin has the potential to antagonize the action of insulin on glucose metabolism by increasing hepatic glucose production and by decreasing muscle, but not adipocyte glucose uptake. For these reasons, it has been suggested that amylin might be involved in the pathophysiology of type II diabetes and obesity, disease states which are characterized by abnormal beta-cell function and insulin resistance. In addition, amylin was shown to induce hypocalcaemia by inhibiting osteoclast-mediated bone resorption in a calcitonin-like manner. Therefore, amylin is likely to be involved in both the modulation of glucose and calcium metabolism.
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PMID:Biological action of pancreatic amylin: relationship with glucose metabolism, diabetes, obesity and calcium metabolism. 140 45


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