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

Diabetes, known since antiquity, has been defined by glycosuria. In 1886, when Minkowski demonstrated that pancreatectomized dogs developed diabetes, the islets of Langerhans became a focus of the search for an active principle culminating in the discovery and the isolation of insulin in 1921 by Banting, Best and Collip. In 1959, the radioimmunoassay of Yalow and Berson solidified the concept of insulin resistance in non-insulin dependent diabetes (NIDDM). In 1971, the insulin receptor was defined as a cell surface protein that initiated the insulin signal transduction cascade. Today, we know that NIDDM accounts for at least 90% of all diabetes worldwide and involves approximately 100 million people. The microvascular complications of NIDDM are the same as for insulin dependent diabetes (IDDM) and are related to the intensity and duration of hyperglycaemia. Further, it is clear from the Diabetes Control and Complications Trial (DCCT) that all microvascular complications can be reduced with intensive control of the blood glucose. Macrovascular disease is also accelerated in NIDDM, including both hypertension and dyslipidemia. The major risk factor for NIDDM are age, obesity, physical inactivity, and genetic background. The earliest features seen in individuals destined to develop NIDDM is insulin resistance, but for hyperglycaemia to ensure there must be a defect in insulin secretion. Thus, insulin resistance defines the prehyperglycaemic phase of NIDDM, but varying degrees of insulin secretory deficiency define the hyperglycaemic phase. Macrovascular risk occurs throughout the lifetime of the individual, whereas microvascular risk ensues with the inception of hyperglycaemia. Tomorrow, we will understand more clearly whether lifestyle changes, such as diet and exercise, or new classes of drugs, can delay or prevent NIDDM. Clinical trials are now beginning to test whether impaired glucose tolerance (IGT) can be delayed or prevented from moving to overt NIDDM. The genetics of NIDDM are under intense study. Mutations in the insulin receptor lead to NIDDM in a small number of patients, and mutations in the glucokinase gene lead to maturity onset diabetes of the young (MODY). Work is now underway to study other candidate genes as well as work on positional cloning techniques to identify diabetes genetic loci. The hormone Leptin has just been discovered and is a major regulator of body weight. In summary, the most important new emphasis on the treatment of NIDDM is the recognition of the importance of hyperglycaemia and our ability to both treat and possibly prevent this metabolic perturbation. This joins the longer-term emphasis on cardiovascular risk reduction from both treatment and prevention of hypertension and dyslipidemia.
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PMID:Non-insulin dependent diabetes--the past, present and future. 928 27

GDM develops in 1-3% of all pregnancies. Women with GDM are characterized by a relatively diminished insulin secretion coupled with a pregnancy-induced insulin resistance primary located in skeletal muscle tissue. The cellular background for this insulin resistance is not known. The binding of insulin to its receptor and the subsequent activation of the insulin receptor tyrosine kinase have significant importance for the cellular effect of insulin. Thus, the pathogenesis to the insulin resistance was studied by investigating insulin receptor binding and tyrosine kinase activity in skeletal muscle biopsies from women with GDM and pregnant controls. No major abnormalities were found in GDM wherefore it is likely that the insulin resistance is caused by intracellular defects distal to the activation of the tyrosine kinase. Glucose tolerance returns to normal postpartum in the majority of women with GDM. However, previous studies, in populations quite different from a Danish population, have shown that women with previous GDM have a high risk of developing overt diabetes mellitus later in life. Hence, we aimed to investigate the prognosis of women with previous GDM with respect to subsequent development of diabetes and also to identify predictive factors for the development of overt diabets in these women. A follow-up study of diet treated GDM women diagnosed during 1978 to 1985 at the Rigshospital, Copenhagen was performed. Glucose tolerance was evaluated in 241 women (81% of the GDM population) 2-11 years after pregnancy. Abnormal glucose tolerance was found in 34.4% of the women (3.7% IDDM, 13.7% NIDDM, 17% IGT) in contrast to a control group where none had diabetes and 5.3% had IGT. Logistic regression analysis identified the following independent risk factors for later development of diabetes: a high fasting glucose level at diagnosis of GDM, a delivery more than 3 weeks before term, and an abnormal OGTT 2 months postpartum. Low insulin secretion at diagnosis of GDM was also an independent risk factor. The presence of ICA and GAD-autoantibodies in pregnancy was associated with later development of IDDM. In another study the following techniques: hyperinsulinaemic euglycaemic clamp, indirect calorimetry and tritiated glucose infusion were used to evaluate insulin sensitivity in glucose tolerant nonobese women with previous GDM and controls. A decreased insulin sensitivity due to a decreased non-oxidative glucose metabolism in skeletal muscle was found in women with previous GDM. Hence, the activity of three key enzymes in intracellular glucose metabolism (GS, HK and PFK) was studied in skeletal muscle biopsies obtained in the basal state and after 3 h hyperinsulinaemia, with the aim to identify the cellular defects causing the decreased insulin sensitivity. However, no abnormalities in enzyme activity was found. The same group of previous GDM women had a relatively reduced insulin secretion evaluated by the IVGTT. A longitudinal study of 91 GDM women showed a relatively reduced insulin secretion to oral glucose in pregnancy, postpartum as well as 5-11 years later. Thus the present review has shown that even nonobese glucose tolerant women with previous GDM are characterized by the metabolic profile of NIDDM i.e. insulin resistance and impaired insulin secretion. Hence, the combination of this finding together with the significantly increased risk for development of diabetes indicates that all women with previous GDM should have a regular assessment of their glucose tolerance in the years after pregnancy. The first OGTT should be performed around 2 months postpartum in order to diagnose women already diabetic and to identify women with the highest risk for later development of overt diabetes. Women with previous GDM comprise a target group for future intervention trials with the aim to prevent or delay development of NIDDM and IDDM.
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PMID:Gestational diabetes mellitus and subsequent development of overt diabetes mellitus. 985 Aug 11

Familial risk, pathogenesis, clinical onset, and treatment of diabetes mellitus vary according to etiology. Although Type 2 diabetes has a higher familial risk, more is known about the genetics of Type 1 diabetes. Genes contributing 60% to 65% of susceptibility to Type 1 diabetes mellitus are known. Type 1 diabetes is associated with susceptibility genes in the HLA region on chromosome 6p21 and the insulin gene on chromosome 11p15, and at least eight additional susceptibility genes are under investigation. Islet cytoplasmic antibodies provide humoral evidence of Type 1 diabetes risk. Only 10% of the genes contributing susceptibility to Type 2 diabetes mellitus are known, and they are primarily associated with uncommon subtypes of the disorder. The insulin receptor gene on chromosome 19p13 and at least five glucose transporter genes contribute to Type 2 diabetes susceptibility, and further associations may emerge from study of the glycogen synthase gene, the glucokinase gene, the MODY genes, and the leptin gene. Diabetes comorbidities may result from genetic and environmental susceptibilities independently or in combination.
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PMID:The genetic basis of diabetes mellitus. 985 64

We described the clinical significance of the measurement of insulin receptors and the mechanism of non-insulin dependent diabetes mellitus (NIDDM). Changes in insulin receptor (IR) of red blood cells in 47 patients with NIDDM were compared with those of 28 normal controls. The levels of high and low-affinity IR in the 47 patients with NIDDM were lower than those of normal controls and were prominent in untreated new NIDDM patients. Hyperinsulinemia was not found in these patients, indicating that the low IR is a primary defect not caused by the "down regulation" mechanism. In the IDDM patients the levels of high and low-affinity IR were higher than those of the normal controls, but decreased markedly after insulin therapy, indicating that the "up regulation" is attributable to the high IR levels, other than the primary IR defect.
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PMID:[Insulin receptors in diabetes mellitus]. 1043 71

Mutations in the insulin receptor gene cause the severe insulin-resistant syndromes leprechaunism and Rabson-Mendenhall syndrome, whose metabolic features include fasting hypoglycemia, post-prandial hyperglycemia, and extremely elevated insulin levels. Patients with Rabson-Mendenhall syndrome have a protracted course and eventually develop ketoacidosis. To determine the mechanism causing this progression and the paradoxical fasting hypoglycemia, we conducted a retrospective study in a patient with Rabson-Mendenhall syndrome, who was a compound heterozygous for two missense mutations affecting the kinase domain of the insulin receptor beta-subunit (I1115T and R1131W). At birth, the patient had fasting hypoglycemia and postprandial hyperglycemia. This was followed at approximately 3 yr of age by constant hyperglycemia and, at 6 yr of age, by constant ketoacidosis. Urinary organic acids during ketoacidosis resembled those of patients with type 1 diabetes. Plasma glucose levels increased (r2 = 0.31; P < 0.01), whereas insulin levels decreased with age (r2 = 0.51; P < 0.01). During periods ofhypoglycemia and hyperglycemia (0-1 yr of age), constant hyperglycemia (3-4 yr of age), and hyperglycemia with ketoacidosis (6-7 yr of age), insulin levels were significantly correlated with plasma glucose levels (P < 0.05). However, the slope of the regression and the predicted insulin level at zero glucose decreased with increasing age. When insulin levels were normalized for the plasma glucose concentrations, an exponential decrease in the insulin/glucose ratio was observed (r2 = 0.92; P < 0.01), with most of the decline occurring before 2 yr of age. These results indicate that the paradoxical fasting hypoglycemia of patients with Rabson-Mendenhall syndrome is associated with severely increased levels of circulating insulin and that the progression of this disease is due to a decline in insulin levels.
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PMID:Progressive decline in insulin levels in Rabson-Mendenhall syndrome. 1044 50

Treatment of type 1 diabetes mellitus has made tremendous advances within the last decades. With concern to insulin delivery there are two promising new approaches. One is the intrapulmonary insulin delivery which has become feasible by the development of new inhalation devices which provide a sufficient degree of intrapulmonary drug retention. Also oral insulin delivery seems feasible when surface active substances are used to cross the mucosal membrane in the gut. Clinical research has also focussed on coatings for the insulin molecules to solve the problem raised by the proteolytic activity of the digestive system. A very new agent produced by a fungus called Pseudomassaria has been demonstrated to reverse the clinical signs of diabetes mellitus in mice. The compound diffuses through the cell membrane, binds to the inner part of the insulin receptor and activates the insulin typical biological effects. Nowadays a variety of insulin analogs are designed and tested for their clinical use. By shifting the isoelectric point towards to a slightly acidic pH, HOE 901 precipitates at physiologic pH resulting in a constant and peakless insulin delivery. NN 304 is a 14-carbon aliphatic fatty acid acylated analog that binds to serum albumin resulting in a flatter time-action profile than NPH insulin. Also rapid acting insulin analogs are or will be launched in the near future aiming to ensure an improved postprandial glucose regulation. Glucagon-like peptide-1 (GLP-1) improves metabolic control by a variety of effects, e.g. the enhancement of insulin secretion and inhibition of glucagon secretion. Moreover, GLP-1 reduces food and water intake controlled by the brain, and inhibits gastric emptying. A disadvantage of GLP-1 is its very short half-life. Novel derivatives with the beneficial effects of GLP-1 but a better resistance against degradation have been designed. In addition substances have been developed inhibiting GLP-1 degradation or augmenting GLP-1 release from its abundant endogenous pool. Finally, there is a variety of interesting approaches aiming to improve or ease blood glucose self-monitoring. One is the development of subcutaneous catheters for continuous blood glucose control. In another system reverse iontophoresis is used for sampling interstitial fluid which reflects capillary blood glucose levels. Instead of using an electric current, a brandnew system creates micropores in the skin by a laser ablation system. Through these micropores a specific device performs a mild suction to obtain intersitial fluid. Further systems which measure blood glucose by near infrared spectroscopy are still investigated in order to improve their technical function and to reduce their weight. This article intends to give an overview over the new developments in the treatment and management of type-1-diabetes mellitus.
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PMID:New developments in the treatment of type 1 diabetes mellitus. 1052 18

Although diabetes is a heterogeneous condition, IGF-I has been shown to improve glycaemic control and reduce insulin requirements in both IDDM and NIDDM. In IDDM, the therapeutic rationale for IGF-I is as a replacement therapy "topping up" low circulating IGF-I levels. There is now convincing evidence that this is associated with a reduction in GH secretion resulting in an improvement in insulin sensitivity and glycaemic control. The mechanism may simply be reduced GH-secretion, but pre- and post-receptor effects on insulin sensitivity are also likely. It is not clear what effect IGF-I treatment has on IGF binding proteins, but with the restoration of a more normal GH/IGF-I axis they are likely to be restored to normal concentrations which may in turn have a direct effect on glucose metabolism. In NIDDM, the mechanism of action of IGF-I remains unclear. At high doses, IGF-I may mimic insulin, but at levels resulting in unacceptable "acromegalic" IGF-I levels and side-effects. The most exciting data concerning IGF-I is with a low dose where IGF-I improves insulin sensitivity by an unknown mechanism. This may be mediated via the IGF-I receptor, by cross-reactivity with the insulin receptor, or by activation of hybrid receptors. The exact mechanism and interaction remains to be elucidated. In severe insulin-resistant states, IGF-I-treatment appears to be effective, and may be the only realistic therapeutic measure in the near future, and warrants further investigation. Detailed genetic characterization of these syndromes following treatment with IGF-I may also help to characterize the mechanism of action of IGF-I and its interactions with the insulin receptor. Thus, IGF-I appears to have a future as a therapeutic agent in treating diabetes, but long-term studies addressing safety and short-term studies addressing mechanisms are essential. With only a few pharmaceutical companies having the capability to produce IGF-I for scientific and therapeutic investigation, it is important that short-term marketing strategy does not prevent the proper exploration of this exciting peptide hormone as a therapeutic agent for all types of diabetes.
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PMID:Insulin-like growth factor-I and diabetes. A review. 1098 75

Diabetes mellitus can be frustrating to treat in veterinary practice, but botanical and nutritional supplements may offer assistance in stabilizing difficult patients. While dogs are typically subject to type 1 diabetes, cats develop type 2 diabetes as much as 70 percent of the time. Whereas treatment adjuncts to insulin may address carbohydrate metabolism from glucose absorption to insulin receptor function, success may depend on the type of diabetes present in the patient.
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PMID:Nutrients and botanicals in the treatment of diabetes in veterinary practice. 1159 Nov 70

Nosologically, Alzheimer disease may not be considered to be a single disorder in spite of a common clinical phenotype. Only a small proportion of about 5% to 10% of all Alzheimer cases is due to genetic mutations (type I) whereas the great majority of patients was found to be sporadic in origin. It may be assumed that susceptibility genes along with lifestyle risk factors contribute to the causation of the age-related sporadic Alzheimer disease (type II). In this context, the desensitization of the neuronal insulin receptor similar to not-insulin dependent diabetes mellitus may be of pivotal significance. This abnormality along with a reduction in brain insulin concentration is assumed to induce a cascade-like process of disturbances including cellular glucose, acetylcholine, cholesterol, and ATP associated with abnormalities in membrane pathology and the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein. Sporadic Alzheimer disease may, thus, be considered to be the brain type of diabetes mellitus II. Experimental evidence is provided and discussed.
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PMID:The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. 1195 56

Several lines of evidence suggest that the aetio-pathogenesis of the common form of type 2 diabetes mellitus and its intrinsically related features of impaired insulin secretion and decreased insulin sensitivity (insulin resistance) includes a strong genetic component. At present, however, little is known about the nature of this genetic component although familial clustering of the disease has been described for decades. Major break-throughs in the genetic sciences of type 2 diabetes have been identifications of insulin receptor gene mutations in syndromes of severe insulin resistance and mutations in pancreatic beta-cell genes in the monogenic sub-group of type 2 diabetes: maturity-onset-diabetes-of-the-young, MODY. Pathophysiological models of insulin resistance in skeletal muscles and impaired glucose-induced insulin secretion in the beta-cells have formed a basis for selecting candidate genes with potential influence on the development of type 2 diabetes ("diabetogenes"). This process of selecting and analyzing genes for mutations that potentially associate with either type 2 diabetes mellitus, insulin resistance or impaired insulin secretion is often described as the "candidate gene approach". The studies reported in this thesis are excerpts from an extensive strategy of genetically dissecting (mutation analysis) in: 1) patients with the common form of late-onset type 2 diabetes mellitus the pathways that transduce the insulin signals from the plasma membrane to the activation of glycogen synthesis in skeletal muscle, and in 2) patients with either late-onset type diabetes or MODY the pathways involved in normal beta-cell development and beta-cell function (insulin secretion). Twelve of the genes that encode proteins in the insulin-signalling pathway from the insulin receptor through the phosphatidylinositide-regulated kinases down to the complex of phosphatases that regulate glycogen synthesis in skeletal muscle were analyzed. We could not confirm that a Val985Met variant in the insulin receptor is associated with type 2 diabetes or that the Met326Val of the p85 alpha regulatory subunit of the phosphoinositide-3 kinase is associated with insulin resistance. We found no coding mutations (missense) in the insulin signalling protein kinases but we confirmed that the 5 bp deletion (PP1ARE) in the 3'-end of the PPP1R3 gene that encodes the glycogen-associated regulatory subunit of protein phosphatase-1 (PP1G) is associated with insulin resistance estimated as insulin mediated glucose uptake. In contrast to protein kinases in skeletal muscles the genes encoding beta-cell transcription factors (IPF-1, NeuroD1/BETA2, and Neurogenin 3) are polymorphic but we could not confirm that the Asp76Asn of IPF-1 is a susceptibility gene for late-onset type 2 diabetes. On the other hand we confirmed that the Ala45Thr variant in NeuroD1/BETA2 may represent a susceptibility gene for type 1 diabetes but none of these genes revealed any MODY-specific mutations. Also the gene encoding the ATP-regulatable potassium channels of the beta-cell (Kir6.2) is polymorphic but none of these polymorphisms associated with changes in glucose-induced insulin secretion. Reviewed in context of the existing data our studies support the candidate gene approach as a feasible method for directly either identifying or excluding any gene as a diabetes-susceptibility gene ("diabetogene").
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PMID:Candidate genes and late-onset type 2 diabetes mellitus. Susceptibility genes or common polymorphisms? 1469 50


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