Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first disease due to disturbances in a cell organelle was discovered in 1959-62, and its basis was loose-coupling of oxidative phosphorylation in the skeletal muscle mitochondria accompanied by severe alterations of their structure (Luft's disease). During the 1980s, functional disturbances and structural alterations in the mitochondria were observed in more than 100 disease entities, mainly in parts of the central nervous system and skeletal muscles. A second breakthrough in this area was the discovery in 1963-64 that mitochondria had their own DNA, mtDNA. Following the observation in 1988 of mutations of mtDNA in mitochondrial diseases, such mutations--mainly deletions and point mutations--were observed in almost all mitochondrial diseases. A remarkable extension of the area is the notion that "normal" ageing is accompanied by decreased oxidative phosphorylation and the appearance of mtDNA mutations. During the last two years, such changes have been demonstrated in diseased states in tissues and organs, which are especially reliant on oxygen supply: in the central nervous system (Parkinson's disease, some types of epilepsy and seizures, Huntington's disease, possibly also in Alzheimer's disease); in heart muscle (cardiomyopathies) and in skeletal muscle. Type 2 diabetes or NIDDM engages two tissues most reliant on oxygen consumption, the pancreatic islets (insulin secretion) and skeletal muscle (insulin sensitivity). Both these functions are genetically determined, the latter to a high degree also controlled by "environmental" factors. The evident age factor in the development of NIDDM could be on a par with the "normal" ageing process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Physiopathology of mitochondria. From Luft's disease to aging and diabetes]. 836 14

Studies employing nonselective serotonin 5-HT(2C) receptor agonists and antagonists have implicated this receptor subtype in many of the actions of serotonin. To further examine the function of this receptor, 5-HT(2C) receptor mutant mice were generated; studies of these animals reveal pleiotropic neurobehavioural effects of the mutation. Three examples are described: (1) Mutants exhibit chronically elevated food intake and the development of an obesity syndrome during the 'middle-age' portion of their lifespan. Their potential utility as a model of human obesity is further indicated by their enhanced sensitivity to high-fat feeding, leading to the development of type 2 diabetes. (2) 5-HT(2C) receptor mutants also display infrequent and sporadic spontaneous seizures. Further studies suggested the presence of globally enhanced neuronal network excitability in these mice. These findings raise the possibility that 5-HT(2C) receptors mediate a role for serotonin in the suppression of seizure activity. (3) Behavioural analysis of mutant mice revealed abnormal performance in a spatial learning task and altered exploratory behaviour, associated with perturbed long-term potentiation restricted to the dentate gyrus perforant path synapse. Taken together, the above findings implicate 5-HT(2C) receptors in the serotonergic regulation of feeding, neuronal network excitability, and hippocampal function.
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PMID:Knockout Corner: Neurobehavioural consequences of a serotonin 5-HT(2C) receptor gene mutation. 1128 72

Spontaneously diabetic cynomolgus monkeys (Macaca fascicularis) exhibit a condition similar to human type 2 diabetes. These monkeys have been maintained by treatment with insulin therapy based on fasting blood glucose levels and glycosylated hemoglobin (HbA1c) values, which are determined periodically by blood sampling. Instead we sought to determine whether the MiniMed Continuous Glucose Monitoring System (CGMS, MiniMed Inc., Sylmer, Calif.), which takes glucose measurements continually over 24 h, would facilitate monitoring and treatment in diabetic cynomolgus monkeys. We attached the CGMS to five diabetic monkeys and obtained their blood glucose profiles. The performance of the CGMS was evaluated against blood glucose values obtained using a palm-sized blood glucose meter. The CGMS accurately measured the animals' blood glucose levels, with a median correlation of 0.95 and a mean absolute difference of 8.2% +/- 4.7% in comparison to the hand-held blood glucose meter. The diabetic monkeys were monitored two or three times during the 3-month study period. Throughout the study, the feeding time, dosage, and insulin administration time were changed in three of the five monkeys in light of the monitoring results. HbA1c levels were measured before and at 1 and 3 months after insulin adjustment. Although the adjusted dosage was not significantly different from the preceding one, HbA1c levels decreased from 7.6% +/- 1.3% to 6.5% +/- 1.1% (P < 0.05) by the end of the study. We concluded that the values from the CGMS closely correlated with those obtained with the hand-held blood glucose meter. Using the CGMS to determine blood glucose profiles allows the blood glucose levels of the monkeys to be monitored during the night as well as the day. Therefore, such continuous monitoring is useful in preventing nocturnal hypoglycemia and hypoglycemic seizures and may facilitate successful management of diabetes.
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PMID:Subcutaneous continuous glucose monitoring and dose adjustment decreases glycosylated hemoglobin in spontaneously diabetic cynomolgus monkeys. 1451 May 23

Dexamethasone-cyclophosphamide pulse (DCP) is the prefered mode of therapy in pemphigus in India because it is relatively free from the side effects seen with heavy doses of daily oral steroids. One hundred forty-six pemphigus patients treated with DCP were observed for side effects of this regimen. One hundred forty mg of dexamethasone was administered IV in 200 ml of 5% dextrose over a period of 60-90 minutes on 3 consecutive days. Five hundred mg of cyclophosphamide was added on first day of the pulse and 50 mg given orally daily in the intervening period. DCP was repeated every 4 weeks and continued for 6 months after subsidence of the disease (no new lesions). Flushing over the face was the most common event recorded during the adiministration in 78 subjects followed by palpitations in 11, hiccups in 9, and numbness of feet in 6. Fourteen patients had polyurea, and 3 developed skin rash. Shivering, shooting pains along thighs, breathlessness, seizure and unilateral limb edema were observed in one patient each. Generalized weakness/malaise was the most troublesome delayed side effect in 81 (55.4%) patients; it lasted for 8-15 days after the pulse. Thirty-six (24.6%) had inadequate sleep syndrome, 23 (15.7%) had headache, 21 (14.3%) complained of arthralgias, 19 (13%) experienced alteration in taste, and 13 (9%) had diffuse hair loss. 28 females developed menstrual disturbances, and 14 (9.5%) had blurring of vision (glaucoma in 3 and posterior subcapsular cataract in 1). Thirteen of eighteen diabetics had an increase in blood sugar requiring higher doses of insulin. Five NIDDM patients needed insulin. Four (2.7%) developed hypertension. Pulse therapy is not absolutely free from side effects. Hypertension and diabetes occur less frequently as compared to conventional steroid therapy. Generalized weakness, flushing, headache and taste alteration occur exclusively with pulse therapy.
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PMID:Immediate and delayed complications of dexamethasone cyclophosphamide pulse (DCP) therapy. 1468 52

Glucokinase (GK) is a glycolytic key enzyme that functions as a glucose sensor in the pancreatic beta-cell, where it governs glucose-stimulated insulin secretion (GSIS). Heterozygous inactivating mutations in the glucokinase gene (GCK) cause a mild form of diabetes (maturity-onset diabetes of the young [MODY]2), and activating mutations have been associated with a mild form of familial hyperinsulinemic hypoglycemia. We describe the first case of severe persistent hyperinsulinemic hypoglycemia due to a "de novo" mutation in GCK (Y214C). A baby girl presented with hypoglycemic seizures since the first postnatal day as well as with inappropriate hyperinsulinemia. Severe hypoglycemia persisted even after treatment with diazoxide and subtotal pancreatectomy, leading to irreversible brain damage. Pancreatic histology revealed abnormally large and hyperfunctional islets. The mutation is located in the putative allosteric activator domain of the protein. Functional studies of purified recombinant glutathionyl S-transferase fusion protein of GK-Y214C showed a sixfold increase in its affinity for glucose, a lowered cooperativity, and increased kcat. The relative activity index of GK-Y214C was 130, and the threshold for GSIS predicted by mathematical modeling was 0.8 mmol/l, compared with 5 mmol/l in the wild-type enzyme. In conclusion, we have identified a de novo GCK activating mutation that causes hyperinsulinemic hypoglycemia of exceptional severity. These findings demonstrate that the range of the clinical phenotype caused by GCK mutations varies from complete insulin deficiency to extreme hyperinsulinemia.
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PMID:Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. 1527 2

Photosensitivity or photoparoxysmal response (PPR) is a common and highly heritable electroencephalographic trait characterized by an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. PPR occurs frequently associated with idiopathic generalized epilepsies (IGEs). The present genomewide linkage scan was designed to map susceptibility loci for PPR and to explore their genetic relationship with IGE. The study included 60 families with at least two siblings displaying PPR. To dissect PPR-specific and IGE-related susceptibility loci, we defined two distinct family subgroups, comprising 19 families with predominantly pure PPR and photosensitive seizures (PPR-families) and 25 families, in which PPR was strongly associated with IGE (PPR/IGE-families). MOD score analyses provided significant evidence for linkage to the region 6p21.2 in the PPR-families (empirical p = 0.00004) and suggestive evidence for linkage to the region 13q31.3 in the PPR/IGE families (p = 0.00015), both with a best-fitting recessive mode of inheritance. In the PPR/IGE-families, linkage evidence was even stronger (p = 0.00003) when the trait definition was broadened by IGE traits. Our study shows two PPR-related susceptibility loci, depending on the familial background of IGE. The locus on 6p21.2 seems to predispose to PPR itself, whereas the locus on 13q31.3 also confers susceptibility to IGE.
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PMID:Genetic dissection of photosensitivity and its relation to idiopathic generalized epilepsy. 1592 39

The WHO announced diabetes mellitus as one of the main threats to human health in the 21st century. In children and adolescents the prevalence of both the autoimmune type 1 and the obesity-related type 2 diabetes is increasing. Common to all types of diabetes is an absolute or relative lack of insulin to keep glucose homeostasis under control. Thus children and adolescents with newly diagnosed diabetes present with hyperglycemia which is often accompanied by ketoacidosis bearing the risk of cerebral edema. Children and adolescents with known diabetes treated with insulin or orale antidiabetic agents may also suffer from hyperglycemia or even ketoacidosis during times of non-compliance with diet and drugs or during concomitant illnesses. Hyperglycemia with ketoacidosis is an emergency situation for which patients need to be admitted to the next hospital for administration of insulin, fluids and potassium. In contrast, insulin treatment in diabetic patients may also lead to a hypoglycemia, the sudden drop in blood glucose, at any moment. Thus recognition and correction of mild hypoglycemia should be familiar to every diabetic child and their caretaker. Severe hypoglycemia with or without seizures may bring the diabetic child in a sudden emergency situation for which the administration of glucagon intramuscularly or glucose intravenously is mandatory. After every severe hypoglycemia the insulin and diet regimen of the diabetic child or adolescent must be reviewed with the diabetes specialist. For unexplained hypoglycemia or major treatment adjustments the diabetic child or adolescent may need to be readmitted to the diabetic ward of a hospital to avoid repeat, potentially life-threatening hypoglycemia.
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PMID:[The diabetic child in the emergency room]. 1613 23

Systemic disease, either genetic or acquired, may prevent or decrease the severity of another disease. These observations have led to important therapeutic advances. The best-known examples are Edward Jenner's use in 1798 of cowpox to prevent smallpox and J.B. Haldane's 1942 observation that erythrocyte disorders such as thalassemia and sickle cell disease modify the severity of malaria. Patients with and carriers of cystic fibrosis may have genetic resistance to tuberculosis and/or secretory diarrhea. The beneficial effects of undernutrition have led to therapeutic diets for seizures, celiac disease, type 2 diabetes, and inflammatory bowel disease. Finasteride for prostatic hypertrophy was developed after the observation that patients with male pseudohermaphrodism resulting from 5-alpha-reductase mutations do not develop prostatic hypertrophy. Rh immunoglobulin for Rh hemolytic disease prevention followed the observation that ABO incompatibility prevented Rh sensitization. The natural immunosuppression of measles may cause remission of nephrosis, and that of leprosy prevents psoriasis. Patients with one form of agammaglobulinemia (X-linked) never get Epstein-Barr virus infection, and patients with another form (common variable) are seemingly cured by HIV infection. HIV/AIDS is prevented or modified by co-receptor mutations (notably the CCRDelta32 chemokine mutation), HIV-2, or GB virus C infection. Additional exploration of these genetic, infectious, and metabolic influences on disease severity may provide new therapeutic approaches to HIV and other diseases.
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PMID:Disease versus disease: how one disease may ameliorate another. 1639 76

Mitochondrial disorders are an uncommon, but important, cause of stroke-like clinical and imaging presentations in individuals under the age of 45 years. We present a 31-year-old man with a 4-year history of migraine-like headaches, type 2 diabetes mellitus, seizures, and hearing loss. Magnetic resonance imaging revealed multiple hyperintensities on T2 and fluid-attenuated inversion recovery sequences. An exhaustive work-up for vasculitis including brain biopsy was performed. Mitochondrial DNA testing revealed the A3243G substitution associated with the mitochondrial encephalomyopathy with lactic acidosis and stroke syndrome. In this case review we briefly discuss the signs and symptoms, frequency, pathophysiology, and prognosis of this disorder.
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PMID:Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS). 1640 Mar 2

An 80-year-old man with a history of Type 2 diabetes mellitus was hospitalized due to generalized convulsive status epilepticus. Initially, hyperglycemia and ketoacidosis were diagnosed, but his seizures were refractory to the medical treatment. Additionally, a high level of serum theophylline (29.1 mg/mL) was detected. Following detoxification of theophylline by oral activated charcoal, the patient regained consciousness and was free from seizures without antiepileptic drug treatment. Brain magnetic resonance imaging revealed subacute subdural hematomas at the bilateral occipital hemispheres. This case suggests that theophylline toxicity may be a predisposing factor for seizures in patients with a history of traumatic brain injury in spite of the presence of diabetic ketoacidosis that may have an anticonvulsant action.
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PMID:Status epilepticus associated with initiation of theophylline in an elderly patient with diabetic ketoacidosis. 1755 22


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