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Sphingolipids mediate diverse cellular functions and serve as specific receptors and cell recognition markers muscle relaxant vocal cord cheap mefenamic 500mg otc. They are continuously delivered to the lysosomal compartment in the course of membrane turnover in endocytosis back spasms 22 weeks pregnant buy mefenamic 250 mg without a prescription, phagocytosis spasms with cerebral palsy order mefenamic with mastercard, and by autophagy muscle relaxant 303 discount mefenamic 250mg visa. Exploration of the roles of Antigen presentation Proteases of lysosomal origin, particularly the cysteine proteinases or cathepsins, are responsible for the cleavage of endocytosed protein 12. Mucopolysaccharidoses Mucopolysaccharides, or glycosaminoglycans, are complex linear polysaccharides, composed of repeating units of polar disaccharides which are strongly negatively charged under physiological conditions; glycosaminoglycans contain amino sugars substituents and are often sulphated. When associated with a linear core protein, the glycosaminoglycans form even larger three-dimensional complexes, known as proteoglycans. By virtue of their negative charge and extended structure, proteoglycans attract water molecules and have important gel-like properties. Proteoglycans are essential components of ground substance in intercellular spaces and connective tissue, including cartilage, vitreous humour, and synovial fluid. Lysosomal degradation of the carbohydrate moieties requires the participation of several glycosidases orchestrated in series. Glycoproteinoses Glycoproteins are proteins to which one or more oligosaccharide chains are attached covalently. The carbohydrate moiety is often branched and complex, mediating specific recognition by cell surface receptors. As with the glycosaminoglycans, lysosomal degradation of the carbohydrate element requires the ordered participation of several glycosidases operating in sequence. Deficiency of one glycosidase, in effect, blocks the subsequent release of sugars in the reaction series, thus causing accumulation of oligosaccharides and other complex glycan molecules. All eukaryotic sulphatases, including the eight sulphatases destined for the mammalian lysosome-where they catalyse the removal of sulphate moieties from glycosaminoglycans, glycolipids, and glycopeptides-require the conversion of a conserved cysteine residue to formylglycine for their activation. Deficiency in the precursor of the small sphingolipid activator proteins leads to loss of activity of the cognate hydrolases, whose activity depends on interaction with the activators saposins A to D. Depending on the selectivity of the defect, a distinct disease complex, characterized by accumulation of a broad panel of glycosphingolipids, occurs when these proteins are deficient. A similar phenomenon occurs in the disorders due to saposin deficiencies and may render correct diagnosis difficult for the unwary. Most acid hydrolases are glycoproteins that are specifically targeted to the lysosomal system through interaction between a mannose-phosphate moiety and membrane mannose-phosphate receptors. Functional classification Classification based on the nature of the defect in cell biological terms is particularly relevant in relation to potential therapeutic approaches. Biochemical characterization of storage compounds guided research into discovery of enzyme activities and gene products. Latterly, the pathogenesis of lysosomal diseases in relation to so-called secondary metabolites and their specific roles in signalling and cell biology is receiving attention; investigations are also underway into the effects of storage on membrane flow and trafficking within the cell. Although the amount of storage material that accumulates within lysosomes in the lysosomal diseases may be several hundred- or thousand-fold greater than normal, the absolute amount of material may amount to only a few grams, even in an enlarged viscus such as the spleen, which may exceed 5kg in some disorders. Psychosines (glucosylsphingosine and galactosylsphingosine) appear to interact with receptors on the plasma membrane of human monocytic-lineage cells. This induces smooth muscle proliferation and is thus implicated in the severe systemic and cerebrovascular manifestations that characterize the condition. These biochemical findings may signify new approaches to the understanding of several lysosomal disorders associated with cell loss due to apoptosis and fibroinflammatory responses; since lysolipids diffuse readily from their site of formation, different approaches to their treatment other than targeted enzyme replacement may be appropriate. In neural tissue, several pathological hallmarks such as meganeurite formation and ectopic dendritogenesis accompany the accumulation of a wide assortment of storage compounds. It appears that lysosomal storage gives rise to a generalized defect in the complex traffic flow mediated by the endosomal system with effects on autophagy, signal propagation at the synapse, axonal transport, myelin formation, and arborization of dendrites. Lipid rafts, detergent-resistant islands within the plasma membrane, contain high local concentrations of gangliosides and play an important role in many cell signalling events. Disorders in which autophagy is markedly disturbed, particularly those affecting the nervous system, can lead to mitochondrial dysfunction as a result of impaired clearance of effete and damaged organelles (defective mitophagy). Secondary metabolites and their effects Although there often appears to be an anatomical relationship between the extent of lysosomal storage and the development of overt disease in a particular organ, at present there is little mechanistic understanding of this relationship in molecular terms. Sphingolipids participate in cell recognition events and receptor biology; sphingolipid metabolites (the deacylated lysosphingolipids) also function as signalling molecules in apoptotic and proliferative responses. An early application of this work has been the use of authentic experimental models of some of the more severe storage diseases generated by gene knockout technology, which facilitate research on otherwise inaccessible tissues such as the brain during the development of the storage phenotype. Hypertrophy and fibrosis characterize the organ responses in many lysosomal diseases. Whether the response is mediated at a cellular, paracrine, or endocrine level remains unclear. The clinical presentation of malfunctioning organs in lysosomal storage disorders generally resembles the pathological outcomes of hypertrophy, fibrosis, and organ failure observed in other chronic conditions. Neurological syndromes vary with the anatomical site of greatest injury and with the relative involvement of grey or white matter (neuronopathic or myelination defects). Cardiac involvement leads to hypertrophy, diastolic dysfunction, conduction and rhythm disturbances, as well as thickening of the valves. Respiratory manifestations of the mucopolysaccharidoses are usually first evident as a result of narrowing of large airways, but restricted ventilation due to skeletal disease often supervenes.

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Cane sugar muscle relaxant guardian pharmacy buy mefenamic overnight, principally from tropical countries spasms of the bladder buy mefenamic 500mg without a prescription, represents about 80% of the global market and is generally cheaper to manufacture than beet sugar muscle relaxant medicines discount mefenamic 500 mg online, which has enjoyed political and economic support from local farming systems muscle relaxant veterinary order mefenamic without prescription, generally in nontropical countries. Direct market competition of beet with cane sugar had occurred in postcolonial times because beet sugar-producing countries mitigated losses on exports by high revenue in domestic markets, thus allowing expansion of domestic beet cultivation. Brazil, one of the first since its early Portuguese colonization, and still the largest producer, controls half the global market but pays subsidies measured in billions annually to its sugar industry. Until very recently, a complex tariff rate system providing direct support of domestic sugar production was used in the United States of America, which maintained the price there up to 90% higher than the world market price at an annual charge of 3. Strong subsidies also operated in the European Union, but with a ruling from the World Health Organization some quotas were abolished in 2015. High-fructose corn syrup is now used extensively as a sweetener in drinks and processed foods. In 1970, the average per capita daily consumption in the United States of America of 105 g calorific sweetener contained only 0. An average portion of ketchup sauce contains about 4 g of free sugar; a single can of soda contains up to 40 g sucrose and/or fructose. Depending on the regional manufacturing and local distribution, the most popular international carbonated drinks obtained from one long-established company based in the United States of America contain 100 to 140 g/litre sugar, mostly as fructose. In fact, all the carbohydrate is present as sorbitol-a direct source of fructose. These mints, peppery rather than sweet to the taste, caused seizures and nephrocalcinosis in a strictly controlled and food-conscious mathematician with hereditary fructose intolerance (whose affected brother had died in infancy). In Europe, sugar intake in adults ranges from about 8% of total energy intake in Hungary and Norway, to more than twice this proportion in Spain and the United Kingdom. Intake is relatively greater among children, ranging from about 12% in Denmark, Slovenia, and Sweden, to nearly 25% in Portugal. Generally, consumption of additional sugar is greater in urban compared with rural communities, but this may not hold in countries where production of cane sugar is still a dominant industry, such as Brazil. Control of sugar consumption the World Health Organization and American Heart Association recommend that women consume less than six teaspoons of sugar per day, which amounts to 25 g; men are recommended to ingest no more than nine teaspoons of sugar per day (38 g). The American Academy of Pediatrics recommends that children between 2 and 18 years take in no more than six teaspoons (25 g) per day. It is noteworthy that none of these recommendations apply to sugar that occurs naturally in foods, such as the fructose present in fruits, nuts, and honey. Given the increasing awareness of the growth of sugar consumption, the food and beverage industry is replacing sugar or corn syrup with non-nutritive sweeteners in a range of products that traditionally contained sugar. However, since 2008, sucralose has become the most popular nonsugar sweetener, replacing aspartame to artificially sweeten foods and beverages. Hidden practices also operate in the United States of America, where it has until recently been possible to mislabel foods and greatly minimize their apparent sugar content. Given the strong influence of food labels on the public, the new regulation is likely to have a salutary effect, and particularly for patients with disorders of fructose metabolism. Some consider that sugar sales and promotion will soon be on the wane, but while this seems to be a premature judgement, sugar is starting to rival tobacco in perception as a major public ill in some quarters. Biochemistry of fructose metabolism the pathways of fructose metabolism are summarized in. Phosphorylated forms of fructose are critical intermediates in the glycolytic and gluconeogenic metabolic pathways in all cells. The symptoms occur in adults and children after ingestion of fructose-rich or sorbitol-rich foods and drinks such as apple juice, and usually recede when the sugars are excluded from the diet. Many such individuals, as well as a high proportion of healthy control subjects, have findings suggestive of fructose malabsorption based on hydrogen breath tests, but definitive evidence of true malabsorption is usually lacking. The molecular basis of this syndrome and of the wide variation of tolerance to dietary fructose and its congeners is not known. Given these findings, it is conceivable that genetic variation in the activity of this nutritional regulatory pathway in the intestine accounts for dietary idiosyncrasy to fructose and sucrose in humans. Other studies have suggested that the distal small intestine and colon of patients who experience abdominal flatulence and diarrhoea after ingesting fructose-containing foods contain a bacterial population with enhanced uptake and anaerobic metabolism of fructose. No conclusive evidence has yet been provided to support these observations and more investigative studies are needed in those patients who experience symptoms attributed to malabsorption of this sugar, including measurement of intestinal fructose absorption, metabolism, and transport. Gluconeogenesis from triose phosphates, lactate, glycerol, amino acids, and Krebs cycle intermediates such as oxaloacetate, requires reversal of the committed reactions of glycolysis. It is the enzyme fructose 1,6-diphosphatase that releases the glucose precursor fructose 6-phosphate from fructose 1,6-diphosphate. Thus, when the remaining reactions of glycolysis are reversed, exogenous fructose provides a source of glucose or glycogen. Fructose 1,6diphosphatase is active in the liver, kidney, and intestine, and is a key enzyme of gluconeogenesis. Fructose is then conveyed via the portal bloodstream to the liver, where it is assimilated. The jejunal mucosa and proximal tubule of the kidney are subsidiary sites of fructose metabolism. Assimilation of fructose depends on the concerted activities of the enzymes ketohexokinase (fructokinase), aldolase B, and triokinase, which are expressed specifically in these tissues. Uptake of fructose occurs independently of insulin and its incorporation into intermediary metabolism bypasses the regulation of glycolysis at the level of phosphofructokinase-1.

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In the hepatic bed vasoconstriction occurs which may lead to periportal fibrin deposition spasms in lower back buy 500 mg mefenamic visa, haemorrhage spasms right abdomen discount mefenamic 250 mg visa, and hepatocellular necrosis muscle relaxant rx order mefenamic 250mg without prescription. In pre-eclampsia there is a reduction in uric acid clearance due to impairment of tubular function spasms brain purchase mefenamic toronto. Proteinuria of intermediate selectivity occurs as a result of impaired glomerular filtration. The characteristic renal lesion of pre-eclampsia is glomerular endotheliosis, which involves 14. Cerebral vasoconstriction may occur in the brain resulting in focal ischaemia and abnormal electrical activity, which may trigger seizures (eclampsia). Eclampsia is the occurrence of one or more convulsions, not attributable to other pathology in a patient with pre-eclampsia. Previously pulmonary oedema, mainly as a result of iatrogenic fluid administration, was the main cause of mortality in women with pre-eclampsia. Intracranial haemorrhage is now the leading cause of death in women with pre-eclampsia. Blindness which may be retinal or cortical in origin is a rare, but usually temporary complication of pre-eclampsia. Differential diagnosis Secondary causes of hypertension should be considered particularly if hypertension is diagnosed in the first half of pregnancy and appropriate investigations performed if necessary as detailed in Table 14. In those women with pre-existing disease it may be extremely difficult to differentiate pre-eclampsia from worsening renal disease due to preexisting hypertension and proteinuria. Clinical features the clinical presentation of pre-eclampsia can vary; from the asymptomatic patient with incidental findings of hypertension and proteinuria, to the patient presenting with eclamptic seizures. A protein creatinine ratio greater than 30 mg/mmol is equivalent to a 24-hour urine excretion greater than 300 mg. This should be performed at the time of diagnosis and then fortnightly depending on the findings. In the presence of intrauterine growth restriction, increased frequency of surveillance is recommended with additional Doppler studies of middle cerebral artery and ductus venosus in addition to umbilical artery Dopplers. Impedance to flow in the maternal uterine arteries normally decreases as pregnancy progresses. Increased impedance in the uterine arteries is an early feature of pre-eclampsia detectable on ultrasound. This increased resistance is thought to reflect high downstream resistance due to defective invasion of spiral arteries and failure of these vessels to transform into low resistance vessels. In low-risk women, the risk of severe pre-eclampsia is best predicted by elevation of the pulsatility index in the second trimester (sensitivity 78%, specificity 95%). In women at high risk of pre-eclampsia, the risk is best predicted by elevated resistance index in the second trimester (sensitivity 80%, specificity 78%). It is involved in the regulation of vascular endothelial growth factor dependent angiogenesis and is thought to be a secondary marker for placental dysfunction. Treatment the treatment for pre-eclampsia remains timely delivery of the fetus (and placenta) to minimize maternal complications and maximize fetal gestational age while avoiding morbidity and mortality. No disease-modifying drugs are currently available that target the placenta or pathophysiological processes causing pre-eclampsia. This may include adjustment of medications to optimize medical morbidities including renal disease, blood pressure control in those with chronic hypertension, weight loss, and cessation of potentially teratogenic agents such as warfarin and angiotensin-converting enzyme inhibitors. Calcium supplementation (1 g/day) in women with low calcium diets has been shown to reduce the chances of having a pregnancy complicated by pre-eclampsia. The trial randomized 756 patients to either induction of labour (n = 377 patients) or expectant management (n = 379). The primary outcomes were a composite of adverse maternal outcomes and neonatal respiratory distress syndrome. The trial recruited 703 women and demonstrated that the composite adverse maternal outcome occurred in four (1. As a result, most would continue to advocate expectant management with monitoring until the clinical situation deteriorates. Generally, when blood pressure consistently exceeds 150 mm Hg systolic or 90 mm Hg diastolic treatment with antihypertensives is advocated but treatment should be individualized depending on the clinical picture. A systolic blood pressure over 160 mm Hg is a medical emergency requiring an immediate response due to the risk of haemorrhagic stroke. The main side effect is headache which is often most severe after starting the medication. Long-acting once-daily preparations may reduce the incidence of headache and help with compliance. The concomitant use of nifedipine and magnesium sulphate must be with caution due to the potential risk of serious adverse maternal effects such as hypotension. However, it has a slow onset of action and at higher doses causes sedation and irritability. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics should not be used in pregnancy. Angiotensin converting enzyme inhibitors may result in fetal hypocalvaria and renal defects. These drugs have also been associated with growth restriction, prematurity, persistent patent ductus arteriosus, and neonatal anuria.

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There is currently no unifying mechanism with supportive experimental evidence to explain ectopic hormone production spasms in abdomen buy cheap mefenamic 500 mg on-line. Further information on the control of gene expression and hormone production muscle relaxant herbal supplement buy mefenamic 250mg mastercard, the role of oncogenes spasms under rib cage generic 500 mg mefenamic mastercard, and paracrine growth factors may provide further insight spasms stomach pain buy mefenamic without a prescription. Treatment Treatment of the clinical or biochemical abnormalities associated with endocrinopathies of nonendocrine origin is best directed at the primary disorder. In neoplastic disease, this may involve surgical excision, radiotherapy, or chemotherapy. More specific therapy may be necessary to manage the associated metabolic abnormality until such time as the underlying disorder can be controlled. Particular syndromes of ectopic hormone secretion Ectopic secretion of calciotropic hormones Malignancy is the most common cause of hypercalcaemia in hospital inpatients and may be due to direct tumour spread to the bones or related to ectopically secreted calcium-releasing factors. Other factors can be involved in hypercalcaemia unassociated with osseous metastases. It is not uncommon for 1,25dihydroxyvitamin D3 to be produced by lymphoproliferative tumours, which are either high grade or widely disseminated. These related cytokines cause hypercalcaemia in vivo; lymphotoxin is also produced by cultured myeloma cells in vitro and accounts for the hypercalcaemia seen in this condition. It is important to remember that primary hyperparathyroidism itself is common, particularly in older people; two diseases may coexist. For this reason, primary hyperparathyroidism should always be considered when hypercalcaemia occurs, even if it is in a patient within the setting of malignant disease. Paraneoplastic hypercalcaemia may be either asymptomatic or dominate the clinical picture and be life-threatening as a consequence of dehydration and renal failure. The features of hypercalcaemia and its general management are discussed elsewhere (see Chapter 13. Oncogenic osteomalacia, an acquired phenotype, is a rare syndrome characterized clinically by reduced mineralization of newly formed bone and the features of osteomalacia (including fractures, bone pain, and muscle weakness). It is usually associated with benign mesenchymal or mixed connective tissue tumours (particularly haemangiopericytomas) that have a propensity to arise in the head and neck. Biochemical features of oncogenic osteomalacia include an excessive renal loss of phosphate that results in phosphaturia and hypophosphataemia. The serum calcium level is usually normal and serum alkaline phosphatase is usually elevated. Circulating levels of 1,25-dihydroxyvitamin D3 are usually suppressed (despite ambient hypophosphataemia). These include bronchial carcinoid tumours most frequently, but also include carcinoids at other sites including the foregut, pancreas, and thymus. Hypokalaemic alkalosis is a characteristic finding; the plasma potassium is typically less than 3. This hypokalaemia is in part due to the very high cortisol levels, which have a mineralocorticoid action, and corticosterone and 11-deoxycorticosterone, which may also be produced in excess. The 11-hydroxysteroid dehydrogenase enzyme may also function abnormally, causing decreased inactivation of cortisol and corticosterone. Such sampling should include inferior petrosal sinuses in case of pituitary-dependent disease. Treatment Rapid control of hypercortisolaemia is the initial aim of management following diagnosis. Bilateral adrenalectomy is an alternative approach, but frequently it is not practical for patients with rapidly progressive metastatic disease. It may be possible to embolize the arterial supply of the adrenal gland if patients are not suitable surgical candidates for adrenalectomy. Medical treatment needs to be monitored carefully so that adrenal insufficiency is avoided. The underlying tumour may be resistant to radiotherapy; surgery, although effective when possible, is not always feasible. Patients with ectopic secretion of gonadotrophins usually present with abnormalities in the reproductive system. In turn, testosterone levels reach those of a normal adult, and secondary sexual characteristics develop together with premature skeletal maturity. Usually the tumour is large and of mesenchymal origin, arising in the abdomen or thorax. Symptoms are those of neuroglycopenia-sweating, tachycardia, disorientation, drowsiness, fits, and coma. Histology shows a mesothelioma, a fibrosarcoma, or other sarcoma such as a leiomyosarcoma. The hypoglycaemia is often not responsive to diazoxide, glucagon, octreotide, or corticosteroids. Thus, cerebrospinal fluid concentrations higher than plasma suggest primary central nervous system disease. This most frequently occurs in women, is not associated with eye signs, and is usually associated with modest biochemical abnormalities.

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These measures should be used in combination with lifestyle intervention muscle relaxant antagonist purchase mefenamic paypal, which is recommended for all subjects with impaired glucose tolerance muscle relaxant in surgeries 250 mg mefenamic with mastercard. Long-term monitoring and management should therefore be as for impaired glucose tolerance muscle relaxer 75 mefenamic 500mg fast delivery. To put this in context infantile spasms 2 month old cheap mefenamic 500 mg on line, key aspects of normal metabolism will be briefly reviewed. The islets of Langerhans There are about 1 million islets of Langerhans in the normal adult: insulin is produced by the cells, which make up the bulky core of each islet; cells also synthesize the peptide known as amylin or islet-associated polypeptide. All islet cells are derived embryologically from the buds of gut endoderm which also give rise to the exocrine pancreatic tissue. Insulin inhibits release of glucagon, while glucagon powerfully stimulates insulin secretion-an action exploited in the testing of -cell reserve (see next). Amylin can inhibit insulin and glucagon secretion as well as reduce appetite and gastric emptying. Its physiological role is uncertain but amylin analogues when used as pharmacotherapy have been shown to reduce weight as well as blood glucose levels. Amylin also polymerizes outside the cell to produce fibrils of amyloid material, which have been implicated in the progressive -cell damage of type 2 diabetes. The precursor molecule, proinsulin, consists of the A and B chains linked end-to-end through a connecting (C) peptide which is cleaved off during insulin processing. In the circulation, insulin is monomeric but in crystals and more concentrated solutions Selfassociation influences the pharmacokinetic properties of subcutaneously injected insulin: the rate-limiting dissociation of hexamers into monomers slows the absorption of even fast-acting insulin. Insulin regulates metabolism in birds, fish, and reptiles as well as mammals, and its structure is remarkably well conserved across the phyla. Three species of insulin are used therapeutically; the human sequence differs from porcine at a single residue (B30) and from bovine at two others. These differences affect the pharmacokinetic and immunogenic characteristics of the insulins (see next). Proinsulin is converted into insulin by the proteolytic excision of the C-peptide chain; the two intermediate cleavage products (with either end of the Cpeptide remaining attached to insulin) are called split products of proinsulin. Normally, almost all proinsulin is processed through this regulated pathway to yield equimolar amounts of insulin and C-peptide. However, its structure is also conserved across species and it may have vasoactive and other properties. These conditions are inherited as autosomal dominant traits; circulating insulin-like or proinsulin-like immunoreactivities may be extremely high, but glucose intolerance is often surprisingly mild. Insulin secretion Glucose is the main insulin secretagogue; this action of glucose is modulated by other ingested nutrients, by hormones released by the islets and the gut, and by the autonomic innervation of the islet. The process gives insight into the mode of action of the sulphonylureas and related drugs, and some of the causes of maturity-onset diabetes of the young and neonatal diabetes (see next). Glucose-stimulated insulin secretion the amount of insulin released by the normal cell is tightly coupled to blood glucose levels and begins to increase immediately when blood glucose rises. Ca2+ ions then flood into the cell from the outside and activate the contractile proteins which drag the secretory vesicles containing insulin and C-peptide to the cell surface. Here, the vesicles fuse with the cell membrane and release their contents into the extracellular space (exocytosis), from where insulin and C-peptide enter the islet capillaries. Repaglinide also closes this K+ channel, but binds to a different site from the sulphonylureas. By contrast, diazoxide locks the channel open, hyperpolarizing the -cell membrane and inhibiting insulin secretion-hence its use in treating insulinoma. Arginine stimulates insulin secretion, possibly by depolarizing the -cell membrane as it enters the cell (it is cationic). The autonomic nervous system is an important modulator of insulin secretion; it is stimulated by the parasympathetic (vagal) outflow and inhibited by the sympathetic. Vagal stimulation is mediated by acetylcholine acting via muscarinic receptors, while the inhibitory sympathetic neurotransmitter is noradrenaline, interacting with 2-adrenoceptors. Normal pattern of insulin secretion Insulin concentrations in peripheral blood show basal levels of about 10 mU/litre (1 mU/litre is approximately equivalent to 6. This may help to keep the target tissues sensitive to insulin; loss of this pulsatility is an early sign of -cell dysfunction in type 2 diabetes. The insulin response elicited by eating is larger than when an equivalent nutrient load is given intravenously. Peripheral insulin levels are lower than those in the portal vein, into which the islets drain, because up to 30% of insulin is removed on its first pass through the liver-one of the main targets for insulin action. The kidney also actively clears and degrades insulin; the circulating half-life is only a few minutes. C-peptide provides a robust measure of residual -cell function, because it is cleared more slowly than insulin and its plasma concentrations are therefore more stable. C-peptide is generally measured after intense -cell stimulation with the powerful insulin secretagogue glucagon; alternatives are a heavy oral load of carbohydrate, mixed meal stimulation including amino acids (such as Boost or Sustacal) or simply the measurement of 24-h secretion of C-peptide in urine (it is cleared largely intact through the kidneys). In normal subjects and most with type 2 diabetes, peak C-peptide concentrations at 6 min after 1 mg of intravenous glucagon are 1 to 4 nmol/litre, whereas type 1 diabetic individuals are typically C-peptide negative, with peak levels less than 0. At diagnosis of type 1 diabetes there may be overlap with levels in patients with type 2 diabetes and accordingly the test is not used diagnostically Insulin receptors are found in the obvious insulin target tissues (fat, liver, and skeletal muscle) but also in unexpected sites, such as the brain and gonads, in which glucose uptake does not depend on insulin.

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