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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Appropriate insulin therapy is central to the management of all individuals with type 1 diabetes mellitus. The potential role of adjunctive therapy in type 1 diabetes is to improve insulin action, and facilitate the ability of all individuals with type 1 diabetes to achieve and maintain 'better' metabolic control. The landmark clinical trial in type 1 diabetes is the Diabetes Control and Complications Trial (DCCT). The DCCT showed that there is no threshold below which a reduction in glycemia would not provide further benefit against diabetes-related microvascular complications. This study in particular provides the rationale for attempting to achieve as near normoglycemia as possible. We review the use of recognized pharmacologic agents as potential insulin adjunctives in children and adolescents with type 1 diabetes. Adjunctive therapies can be grouped into the following categories based on their putative mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin), and other targets of action (e.g. pirenzepine and insulin-like growth factor-1 [IGF-1], which reduce growth hormone secretion, and glucagon-like peptide-1, which acts to stimulate insulin secretion). Many of these agents have been found to be effective in short-term studies with decreases in glycosylated hemoglobin of 0.5-1.0%, lowered postprandial blood glucose levels, and decreased daily insulin doses. Adverse effects such as poor gastrointestinal tolerability (metformin, acarbose) or potential acceleration of retinopathy (IGF-1) indicates the need for further studies of efficacy, safety, and patient selection before these adjunctive therapies can be widely recommended in type 1 diabetes.
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PMID:Potential adjunctive therapies in adolescents with type 1 diabetes mellitus. 1551 Nov 28

At present, diabetic kidney disease affects about 15-25 % of patients with type 1 diabetes (T1D) and 30-40 % of patients with type 2 diabetes (T2D). Several decades of extensive research have elucidated various pathways to be implicated in the development of diabetic kidney disease. These include metabolic factors beyond blood glucose (e.g. advanced glycation endproducts (AGEs)), haemodynamic factors (e.g. the renin angiotensin system (RAS)), intracellular signaling molecule proteins (e.g. protein kinase C (PKC)) and growth factors/cytokines (e.g. growth hormone (GH), insulin-like growth factors (IGFs), transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF)). This review focuses on the role of three of these growth factors, i.e. GH, IGFs and VEGF. A brief discussion of each system is followed by description of its expression in the normal kidney. Then, for each system, in vitro, experimental and clinical evidence addressing the role of the system in diabetic kidney disease is presented. The interplay of each system to other potential pathways will also be addressed. Finally, well-known and potential therapeutic strategies targeting the GH/IGF and VEGF systems in a specific or indirect way will discussed.
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PMID:The involvement of growth hormone (GH), insulin-like growth factors (IGFs) and vascular endothelial growth factor (VEGF) in diabetic kidney disease. 1554 23

Type 1 diabetes mellitus (T1DM) and other chronic diseases in children are well known to adversely affect linear growth and pubertal development. In the years immediately following the introduction of insulin therapy, short stature was consistently reported in children with T1DM. However, over the past 50 years significant improvement in the prognosis for growth and final height in children with diabetes has been achieved. Although pre-pubertal and post-pubertal growth are important phases in growth, puberty and its related hormonal changes represent a critical phase for growth gain and final height particularly in patients with T1DM. Growth impairment reported in diabetic patients is dependent on abnormalities in physiological bone growth and corresponds to abnormalities of the growth hormone-insulin-like growth-I (GH-IGF-I) axis. These alterations seem to be related to appropriate insulin levels and thereby to glycaemic control as judged by haemoglobin levels. Modern diabetes care, particularly intensified insulin regimens, might improve metabolic control in patients with T1DM, therefore preventing abnormalities of the GH-IGF-I axis and leading to normal growth and final height similar to that of their unaffected peers.
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PMID:Growth, growth factors and diabetes. 1555 95

Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6, prolactin, growth hormone, IL-12, IL-15, granulocyte colony-stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory-immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T-helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro-inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses.
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PMID:Leptin, from fat to inflammation: old questions and new insights. 1564 35

Insmed is developing mecasermin rinfabate, a recombinant complex of insulin-like growth factor-I (rhIGF-I) and binding protein-3 (rhIGFBP-3) [insulin-like growth factor-I/insulin-like growth factor binding protein-3, rhIGF-I/rhIGFBP-3, SomatoKine], for a number of metabolic and endocrine indications. In the human body, IGF-I circulates in the blood bound to a binding protein-3 (IGFBP-3), which regulates the delivery of IGF-I to target tissues, and particular proteases clip them apart in response to stresses and release IGF-I as needed. IGF-I, a naturally occurring hormone, is necessary for normal growth and metabolism. For the treatment of IGF-I deficiency, it is desirable to administer IGF-I bound to IGFBP-3 to maintain the normal equilibrium of these proteins in the blood. Mecasermin rinfabate (rhIGF-I/rhIGFBP-3) mimics the effects of the natural protein complex in the bloodstream and would augment the natural supply of these linked compounds. The most advanced indication in development of mecasermin rinfabate is the treatment of severe growth disorders due to growth hormone insensitivity syndrome (GHIS), also called Laron syndrome. GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature. Mecasermin rinfabate also has potential as replacement therapy for IGF-I, which may become depleted in indications such as major surgery, organ damage/failure, traumatic injury, cachexia and severe burn trauma. It also has potential for the treatment of osteoporosis. Mecasermin rinfabate was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on 1 June 2000. Insmed and Avecia of the UK have signed an agreement for manufacturing mecasermin rinfabate and its components, rhIGF-1 and rhIGFBP-3. CGMP clinical production of mecasermin rinfabate and its components will be carried out in Avecia's Advanced Biologics Centre, Billingham, UK, which manufactures recombinant-based medicines and vaccines at the capacity of up to 1000L. In April 2004, Insmed announced that it acquired a lease to operate the manufacturing facility formerly operated by Baxter for the commercial production of SomatoKine in Boulder, CO, USA. With the two manufacturing facilities for SomatoKine, Insmed plans to meet the development and commercial demands for the product over the next several years. In its 2003 Form-10K, Insmed announced plans to conduct comparative studies with the previously used drug substance and the new substance produced by Avecia. The comparative data will be included in the regulatory filing for mecasermin rinfabate. Mecasermin rinfabate was originally licensed to Welfide for Japan. On 1 October 2001, Welfide Corporation merged with Mitsubishi-Tokyo Pharmaceuticals to form Mitsubishi Pharma Corporation. The new company is a subsidiary of Mitsubishi Chemical. In October 2004, Insmed announced that Tzamal Pharma has been granted exclusive distribution and marketing rights for mecasermin rinfabate in certain Middle Eastern territories including Israel. Tzamal Pharma also acquired exclusive rights to Insmed's named patient programme for the agent in these territories. Tzamal Pharma intends to begin the appropriate registration activities for mecasermin rinfabate in the treatment of children with growth hormone-insensitivity syndrome. This pivotal, 12-month, multicentre, open-label trial in 30 children with GHIS was initiated in June 2003 and was designed to evaluate the safety and efficacy of the agent in prepubescent children with GHIS. The 6-month endpoint data analysis showed that mecasermin rinfabate given as a once-daily injection was safe and well tolerated. The agent demonstrated a significant increase in height velocity in children with GHIS similar to that observed by Pfizer in their pivotal study with twice-daily injections of rhIGF-I. The full results from the pivotal trial are expected in 2005. In April 2003 Insmed initiated a named patient programme in Europe that will make available mecasermin rinfabate for the treatment of GHIS-Laron syndrome. The treatment of patients was initiated in Scandinavia, with authorisation pending in several other European countries. Mecasermin rinfabate will be made available to those GHIS patients who, in the opinion of their doctor, may benefit from IGF-I therapy. At precommercial scale quantities, the drug will be available on a limited basis.A phase II dose-ranging study in children with GHIS was completed at Saint Bartholomew's and the Royal London School of Medicine, London, UK. A single dose of mecasermin rinfabate delivered the same amount of IGF-1 as two daily injections of unbound IGF-1. No adverse events were reported. Insmed has acquired an exclusive licence to Pharmacia's regulatory filings concerning yeast-derived insulin-like growth factor 1 (IGF-1). These filings were used by Pharmacia to receive marketing approvals in several European countries and also in the IND application with the US FDA. Insmed believes that this licence will facilitate the development of mecasermin rinfabate for the treatment of children with GHIS. In January 2003, Insmed announced positive results from a double-blind, placebo-controlled, dose-ranging study of mecasermin rinfabate in adolescent patients with type 1 diabetes receiving insulin therapy. The study was conducted at the University of Cambridge, Cambridge, UK, under supervision of Prof. D. Dunger. The researchers from The Robarts Research Institute and the University of Western Ontario, Canada (leading investigator T.L. Delovitch, the Sheldon H. Weinstein scientist in Diabetes at the University of Western Ontario) have found that mecasermin rinfabate complex was significantly more effective than IGF-1 in reducing the severity of insulitis, beta cell destruction and delaying the onset of type 1 diabetes. The study was supported by grants from Canadian Institutes of Health and the Juvenile Diabetes Research Foundation. Insmed plans to initiate large-scale phase II clinical studies in this indication. At the BIO 2004 Annual International Convention (BIO-2004) in June 2004, Insmed announced that it has received a grant from the US National Institutes of Health (NIH)/Muscular Dystrophy Association (MDA) worth USD $6.5 million to investigate the efficacy of mecasermin rinfabate for the treatment of myotonic dystrophy. It has also been granted orphan drug status for the treatment of GHIS-Laron syndrome in the US and Europe. In December 2003, Insmed announced that mecasermin rinfabate was designated orphan drug status by the FDA for the treatment of extreme insulin resistance. This provides Insmed with 7 years of market exclusivity following approval of mecasermin rinfabate for this indication. Insmed has received orphan drug designation for mecasermin rinfabate in the treatment of extreme insulin resistance in Europe (October 2004). In November 2004, Insmed was granted the European patent EP1183042 entitled "Methods for Treating Diabetes". This patent corresponds with the US patent US 6,040,292 also entitled "Methods for Treating Diabetes". Both patents cover type 1 and type 2 diabetes mellitus and insulin resistant diabetes including type A insulin resistance (the least severe form of extreme insulin resistance syndromes). In January 2004, Insmed obtained a non-exclusive licence to the patents for use of IGF-I for the treatment of extreme or severe insulin-resistant diabetes from Fujisawa Pharmaceutical. Insmed will have worldwide rights in territories (excluding Japan) with existing valid patent claims including the US and Europe. Insmed holds 28 US issued or allowed patents for the composition, production, antibodies and methods of use of mecasermin rinfabate. These US patents expire at various times between the years 2010 and 2019. Insmed through their lawyers filed its defense and counterclaim to the alleged patent infringement brought by Tercica against Insmed in the London High Court of Justice. Insmed asserted that it did not infringe any valid patent claims as none of the claims of the patent were patentable because the subject matter was not new. Insmed also stated that the patent did not involve an inventive step, did not have capability of industrial application and had no clear description of the invention so that invention can be performed by the person skilled in the art. Insmed is seeking revocation of the patent on these grounds.
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PMID:Mecasermin rinfabate: insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3. 1577 6

Diabetic ketoacidosis (DKA) is the most common hyperglycemic emergency in patients with diabetes mellitus. DKA most often occurs in patients with type 1 diabetes, but patients with type 2 diabetes are susceptible to DKA under stressful conditions, such as trauma, surgery, or infections. DKA is reported to be responsible for more than 100 000 hospital admissions per year in the US, and accounts for 4-9% of all hospital discharge summaries among patients with diabetes. Treatment of patients with DKA uses significant healthcare resources and accounts for 1 out of every 4 healthcare dollars spent on direct medical care for adult patients with type 1 diabetes in the US. Recent studies using standardized written guidelines for therapy have demonstrated a mortality rate of less than 5%, with higher mortality rates observed in elderly patients and those with concomitant life-threatening illnesses. Worldwide, infection is the most common precipitating cause for DKA, occurring in 30-50% of cases. Urinary tract infection and pneumonia account for the majority of infections. Other precipitating causes are intercurrent illnesses (i.e., surgery, trauma, myocardial ischemia, pancreatitis), psychological stress, and non-compliance with insulin therapy. The triad of uncontrolled hyperglycemia, metabolic acidosis and increased total body ketone concentration characterizes DKA. These metabolic derangements result from the combination of absolute or relative insulin deficiency and increased levels of counter-regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). Successful treatment of DKA requires frequent monitoring of patients, correction of hypovolemia and hyperglycemia, replacement of electrolyte losses, and careful search for the precipitating cause. Since the majority of DKA cases occur in patients with a known history of diabetes, this acute metabolic complication should be largely preventable through early detection, and by the education of patients, healthcare professionals, and the general public. The frequency of hospitalizations for DKA has been reduced following diabetes education programs, improved follow-up care, and access to medical advice. Novel approaches to patient education incorporating a variety of healthcare beliefs and socioeconomic issues are critical to an effective prevention program.
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PMID:Diabetic ketoacidosis: risk factors and management strategies. 1587 46

Circulating levels of insulin-like growth factor-I (IGF-I) and its principal binding protein IGFBP-3 are reduced, whereas those of the inhibitory binding protein, IGFBP-1, tend to be high in children and adolescents with type 1 diabetes mellitus (T1DM). These abnormalities are thought to arise because of relative portal hypoinsulinaemia and partial resistance at the hepatic growth hormone (GH) receptor. During adolescence, reductions in IGF-I and IGF bioactivity lead to feedback for GH hypersecretion and the elevated GH and low IGF-I levels lead to an increase of the normal insulin resistance encountered during puberty. Low IGF-I levels, but in particular elevated GH levels, have been implicated in the pathogenesis of diabetic microangiopathic complications, in particular, renal hypertrophy, glomerular hyperfiltration and the development of microalbuminuria. Early study of IGF-I replacement with recombinant human IGF-I (rhIGF-I) demonstrated, in the short term, reductions in GH hypersecretion with improved insulin sensitivity and, in the longer term, reductions in insulin requirements and improvements in HbA1c levels. However, larger doses of rhIGF-I were associated with retinopathy either due to rapid improvements in glycaemic control or direct effects of high levels of 'free' IGF-I. More recently, pilot studies using the combination of rhIGF-I/rhIGFBP-3 have confirmed the physiological efficacy of IGF-I replacement in T1DM. The combined treatment is better tolerated and may result in reduced tissue exposure to high levels of 'free' IGF-I. Longer term clinical studies with this IGF-I/IGFBP-3 combination are needed.
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PMID:Childhood and adolescent diabetes. 1587 93

We report a rare case of type 1 diabetes in a woman associated with acromegaly who was treated with surgery after pregnancy. An 18-year-old woman came to our hospital in April, 1998, complaining of thirst, polydipsia, polyuria, appetite loss, body weight loss of 8 kg in a month, and amenorrhea beginning 2 months earlier. Based on laboratory data, she was diagnosed as having type 1 diabetes mellitus. Although we suspected her of having acromegaly because of high growth hormone (GH) levels (6.9 or 8.5 ng/ml), blood levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) were within normal range and the circadian rhythm of her blood GH levels was normally maintained. Her blood GH level was elevated to 12.6 ng/ml 15 minutes after a TRH administration. Blood GH levels were suppressed from 49 ng/ml to 1.5 ng/ml 4 hours after an oral administration of 2.5 mg of bromocriptine. A magnetic resonance images (MRIs) showed pituitary swelling, but no nodules were found in the pituitary. Therefore, we diagnosed her as having acromegaly and observed her without surgery, while prescribing diet therapy and intensive insulin therapy for diabetes. We started a treatment of oral administration of 7.5 mg of bromocriptine per day for the acromegaly from April 28, 2000, because her elevated GH was suspected of causing her diabetes to be poorly controlled. During a pregnancy from October, 2000 to September, 2001, diabetic control was improved with increased administration of insulin under a constant dose of bromocriptine. She delivered a normal full-term infant. After the bromocriptine therapy was stopped as she hoped to breastfeed, blood levels of GH and IGF-1 became elevated and her diabetic control deteriorated. As her pituitary tumor observed in pituitary MRIs became larger during the course, a transsphenoidal surgery was performed on March 8, 2002. After the surgery, blood levels of GH and IGF-1 lowered and diabetic control improved again. We concluded as follows: to rule out acromegaly in patients with poorly controlled diabetes, 1) measurements of serum GH and IGF-1 should be performed, and 2) pituitary MRIs should be performed if blood levels of GH or IGF-1 are high.
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PMID:Type 1 diabetes associated with asymptomatic acromegaly successfully treated with surgery after pregnancy: a case report. 1612 8

The proinflammatory cytokine interleukin-6 (IL-6) may modulate the onset and progression of complications of diabetes. As this cytokine increases after exercise, and many other exercise responses are altered by prior glycemic fluctuations, we hypothesized that prior hyperglycemia might exacerbate the IL-6 response to exercise. Twenty children with type 1 diabetes (12 boys/8 girls, age 12-15 yr) performed 29 exercise studies (30-min intermittent cycling at approximately 80% peak O2 uptake). Children were divided into four groups based on highest morning glycemic reading [blood glucose (BG) < 150, BG 151-200, BG 201-300, or BG > 300 mg/dl]. All exercise studies were performed in the late morning, after hyperglycemia had been corrected and steady-state conditions (plasma glucose < 120 mg/dl, basal insulin infusion) had been maintained for > or = 90 min. Blood samples for IL-6, growth factors, and counterregulatory hormones were drawn at pre-, end-, and 30 min postexercise time points. At all time points, circulating IL-6 was lowest in BG < 150 and progressively higher in the other three groups. The exercise-induced increment also followed a similar dose-response pattern (BG < 150, 0.6 +/- 0.2 ng/ml; BG 151-200, 1.2 +/- 0.8 ng/ml; BG 201-300, 2.1 +/- 1.1 ng/ml; BG > 300, 3.2 +/- 1.4 ng/ml). Other measured variables (growth hormone, IGF-I, glucagon, epinephrine, cortisol) were not influenced by prior hyperglycemia. Recent prior hyperglycemia markedly influenced baseline and exercise-induced levels of IL-6 in a group of peripubertal children with type 1 diabetes. While exercise is widely encouraged and indeed often considered part of diabetic management, our data underscore the necessity to completely understand all adaptive mechanisms associated with physical activity, particularly in the context of the developing diabetic child.
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PMID:Effect of prior hyperglycemia on IL-6 responses to exercise in children with type 1 diabetes. 1633 21

Ghrelin is a newly discovered peptide and an endogenous ligand for growth hormone (GH) secretagogue (GHS) receptor. It has been shown to possess various central and peripheral effects, including GH secretion, food intake, and gastric and cardiac effects. Ghrelin and the GHS receptor are expressed also in pancreatic islets. We have identified several ghrelin-induced genes by PCR-select subtraction methods, among which is a beta-cell autoantigen for type 1 diabetes, IA-2beta. Administration of ghrelin increased IA-2beta mRNA in mouse brain, pancreas, and insulinoma cell lines (MIN6 and betaTC3). However, the expression of IA-2, another structurally related beta-cell autoantigen, was not induced by ghrelin. Administration of ghrelin or overexpression of IA-2beta, but not overexpression of IA-2, inhibited glucose-stimulated insulin secretion in MIN6 insulinoma cells and, moreover, inhibition of IA-2beta expression by the RNA interference technique ameliorated ghrelin's inhibitory effects on glucose-stimulated insulin secretion. These findings strongly suggest that inhibitory effects of ghrelin on glucose-stimulated insulin secretion are at least partly due to increased expression of IA-2beta induced by ghrelin. Our data demonstrate the link among ghrelin, IA-2beta, and glucose-stimulated insulin secretion.
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PMID:IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion. 1641 80


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