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

The nutritional value of glycerol-1,2,3-tris(methylsuccinate), a novel ester of succinic acid with high insulinotropic efficiency both in vitro and in vivo, was assessed in both fed and starved rats. The infusion of the ester, given in a daily amount (1.2 micromol. g body wt-1) well in excess of what could result from its repeated intravenous administration as an insulinotropic agent in non-insulin-dependent diabetes (0.07 micromol. g body wt-1 for each administration), failed to prevent the fall in body weight, liver and muscle glycogen contents, and plasma d-glucose or insulin concentration, as well as the increase in plasma free fatty acid and beta-hydroxybutyrate concentrations caused by starvation. The sole indications that the ester may serve, to a limited extent, as an alternative nutrient in starved rats consisted in a somewhat higher weight of both liver and paraovarian adipose tissue and somewhat higher activity of liver glucokinase in rats receiving the ester than in animals infused with saline. The low nutritional value of this ester thus answers the objection of its possible role as an extrapancreatic nutrient or gluconeogenic precursor in the perspective of its use as an insulinotropic tool in type 2 diabetes.
 ...
PMID:Assessment of the nutritional value of glycerol-1,2, 3-tris(methylsuccinate) in fed and starved rats. 1038 33

The differential diagnosis of hyperglycemia in childhood and adolescence has to take into consideration early-onset non-insulin-dependent diabetes, defined as maturity onset diabetes of the young (MODY). To date, mutations in genes of five proteins have been shown to cause MODY: glucokinase (MODY2), hepatic nuclear factor-1 alpha (HNF-1 alpha) (MODY3), hepatic nuclear factor-4 alpha (HNF-4 alpha) (MODY1), insulin promoter factor 1 (IPF-1) (MODY4) and hepatic nuclear factor-1 beta (HNF-1 beta) (MODY5), but other MODY genes still await elucidation. Clinical and metabolic heterogeneity of these subtypes of type 2 diabetes need to be defined, as deficiency of each factor has its own phenotype. Pediatric diabetologists should be aware of the increasing importance of MODY as a possible cause of hyperglycemia in children and adolescents. This will allow for the early diagnosis of these metabolic conditions and for the appropriate follow-up and treatment.
 ...
PMID:Maturity-onset diabetes of the young (MODY): a new challenge for pediatric diabetologists. 1041 64

Mutations in the glucokinase (GK) gene cause type-2 maturity-onset diabetes of the young type 2 (MODY-2) and GK-linked hyperinsulinaemia (GK-HI). Recombinant adenoviruses expressing the human wild-type islet GK or one of four mutant forms of GK, (the MODY-2 mutants E70K, E300K and V203A and the GK-HI mutant V455M) were transduced into glucose-responsive insulin-secreting beta-HC9 cells and tested functionally in order to initiate the first analysis in vivo of recombinant wild-type and mutant human islet GK. Kinetic analysis of wild-type human GK showed that the glucose S(0. 5) and Hill coefficient were similar to previously published data in vitro (S(0.5) is the glucose level at the half-maximal rate). E70K had half the glucose affinity of wild-type, but similar enzyme activity. V203A demonstrated decreased catalytic activity and an 8-fold increase in glucose S(0.5) when compared with wild-type human islet GK. E300K had a glucose S(0.5) similar to wild-type but a 10-fold reduction in enzyme activity. E300K mRNA levels were comparable with wild-type GK mRNA levels, but Western-blot analyses demonstrated markedly reduced levels of immunologically detectable protein, consistent with an instability mutation. V455M was just as active as wild-type GK, but with a markedly reduced S(0.5). The effects of the different GK mutants on glucose-stimulated insulin release support the kinetic and expression data. These experiments show the utility of a combined genetic, biochemical and cell-biological approach to the quantification of functional and structural changes of human GK that result from MODY-2 and GK-HI mutations.
 ...
PMID:Cell-biological assessment of human glucokinase mutants causing maturity-onset diabetes of the young type 2 (MODY-2) or glucokinase-linked hyperinsulinaemia (GK-HI). 1045 21

Glucagon-like peptide-1 (GLP-1) enhances insulin biosynthesis and secretion as well as transcription of the insulin, GLUT2 and glucokinase genes. The latter are also regulated by the PDX-1 homeoprotein. We investigated the possibility that GLP-1 may be having its long-term pleiotropic effects through a hitherto unknown regulation of PDX-1. We found that PDX-1 mRNA level was significantly increased (p<0.01) after 2 hours and insulin mRNA level was subsequently increased (p<0.01) after 3 hours of treatment with GLP-1 (10 nM) in RIN 1046-38 insulinoma cells. Under these experimental conditions, there was also a 1.6-fold increase in the expression of PDX-1 protein in whole cell and nuclear extracts. Overexpression of PDX-1 in these cells confirmed the finding of the wild type cells such that GLP-1 induced a 2-fold increase in whole cell extracts and a 3-fold increase in nuclear extracts of PDX-1 protein levels. The results of electrophoretic mobility shift experiments showed that PDX-1 protein binding to the Al element of the rat insulin II promoter was also increased 2 h post treatment with GLP-1. In summary, we have uncovered a previously unknown aspect to the regulation of PDX-1 in beta cells. This has important implications in the physiology of adult beta cells and the treatment of type 2 diabetes mellitus with GLP-1 or its analogs.
 ...
PMID:Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells. 1049 50

Zucker diabetic fatty rats develop type 2 diabetes concomitantly with peripheral insulin resistance. Hepatocytes from these rats and their control lean counterparts have been cultured, and a number of key parameters of glucose metabolism have been determined. Glucokinase activity was 4.5-fold lower in hepatocytes from diabetic rats than in hepatocytes from healthy ones. In contrast, hexokinase activity was about 2-fold higher in hepatocytes from diabetic animals than in healthy ones. Glucose-6-phosphatase activity was not significantly different. Despite the altered ratios of glucokinase to hexokinase activity, intracellular glucose 6-phosphate concentrations were similar in the two types of cells when they where incubated with 1-25 mM glucose. However, glycogen levels and glycogen synthase activity ratio were lower in hepatocytes from diabetic animals. Total pyruvate kinase activity and its activity ratio as well as fructose 2,6-bisphosphate concentration and lactate production were also lower in cells from diabetic animals. All of these data indicate that glucose metabolism is clearly impaired in hepatocytes from Zucker diabetic fatty rats. Glucokinase overexpression using adenovirus restored glucose metabolism in diabetic hepatocytes. In glucokinase-overexpressing cells, glucose 6-phosphate levels increased. Moreover, glycogen deposition was greatly enhanced due to the activation of glycogen synthase. Pyruvate kinase was also activated, and fructose-2,6-bisphosphate concentration and lactate production were increased in glucokinase-overexpressing diabetic hepatocytes. Overexpression of hexokinase I did not increase glycogen deposition. In conclusion, hepatocytes from Zucker diabetic fatty rats showed depressed glycogen and glycolytic metabolism, but glucokinase overexpression improved their glucose utilization and storage.
 ...
PMID:Glucokinase overexpression restores glucose utilization and storage in cultured hepatocytes from male Zucker diabetic fatty rats. 1054 7

The transmission disequilibrium test with use of trios (an affected proband with both parents) is a robust method for assessing the role of gene variants in disease that avoids the problem of population stratification that may confound conventional case/control studies and allows the detection of parent-of-origin effects. Trios have played a major role in defining genes in a number of polygenic conditions, including type 1 diabetes. We assessed the prevalence, clinical characteristics, and suitability for defining type 2 susceptibility genes of European type 2 diabetes trios. In a Caucasian population in the U.K., only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy, we collected 182 trios defined by strict clinical criteria. Immunological and genetic testing resulted in the exclusion of 25 trios as a result of latent autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and maternally inherited diabetes and deafness (n = 5). The 157 remaining probands had similar treatment requirements to familial type 2 diabetic subjects but presented at a younger age, were more obese, and more frequently had affected parents. Using this resource, we have not found any evidence for linkage disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2 diabetes trios are difficult to collect but provide an important additional approach to dissecting the genetics of type 2 diabetes.
 ...
PMID:Parent-offspring trios: a resource to facilitate the identification of type 2 diabetes genes. 1058 Apr 39

Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY occurs predominantly in Caucasians and presents before age 25, is nonketotic, and is generally not insulin-requiring. Less than 5% of cases of childhood diabetes in Caucasians are caused by MODY. ADM is a subtype of MODY that occurs in approximately 10% of African-Americans with youth onset diabetes. In contrast to MODY in Caucasians, ADM presents clinically as acute onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis. Approximately 50% of patients with ADM are obese. Therefore, based strictly on clinical grounds, at onset, ADM cannot be distinguished from type 1 diabetes. Months to years following diagnosis, a non-insulin-dependent clinical course develops in patients with ADM that is clearly different from type 1 diabetes. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5). These monogenic forms of MODY have been used as model systems to investigate the inheritance and pathophysiology of type 2 diabetes. Clinicians, should be able to diagnose MODY. Type 1 diabetes, the most common form of diabetes in Caucasians, is always insulin-requiring for control and survival, whereas patients with MODY do not usually require long-term insulin for survival. Diagnostic confusion can lead to inappropriate management and patient expectations. Primary care physicians must be alert to avoid therapeutic confusion when patients with ADM enter into the non-insulin-dependent stage. An approach to the diagnosis of childhood diabetes is offered in Table 4. The majority of youth onset diabetes remains type 1; however, the frequency of type 2 diabetes is rising in obese children and adolescents and especially in obese minority youth. The diagnosis of MODY can be made through a careful review of the patient's clinical course, severity of hyperglycemia, and family history. The identification of islet autoantibodies is confirmatory evidence of autoimmune (type 1) diabetes. Because testing for MODY mutations is expensive and is performed at a select number of research laboratories only, routine molecular genetic studies to search for the various MODY mutations should be limited to research investigations. In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations.
 ...
PMID:Monogenic diabetes mellitus in youth. The MODY syndromes. 1060 19

Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between birth weight and genetically determined defects in insulin secretion, we measured the birth weights of neonates derived from crosses of male pancreatic beta-cell type glucokinase knockout (Gck+/-) mice and female wild-type (WT) or Gck+/- mice. In 135 offspring, birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck-/- neonates had significantly smaller birth weights than WT or Gck+/- neonates (means +/- SE 1.49+/-0.03 [n = 30] vs. 1.63+/-0.03 [n = 30] or 1.63+/-0.02 [n = 50] g, respectively; P<0.01). Thus, Gck mutations in beta-cells may impair insulin response to glucose and alter intrauterine growth as well as glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth. Moreover, birth weights were reduced in insulin receptor substrate-1 knockout mice despite normal insulin levels. Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes.
 ...
PMID:Insulin effect during embryogenesis determines fetal growth: a possible molecular link between birth weight and susceptibility to type 2 diabetes. 1061 53

The maturity-onset diabetes of the young (MODY), an autosomal dominant form of non-insulin dependent diabetes mellitus (NIDDM), is caused by mutations in the glucokinase (GK, MODY 2) and in the hepatocyte nuclear factor 1a (MODY 3) and 4a (MODY 1) genes. We have screened the glucokinase gene by the polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE) in fifteen subjects with clinical characteristics of MODY and one parent with NIDDM, impaired glucose tolerance or gestational diabetes. PCR products with abnormal mobility in DGGE were directly sequenced. We have identified four mutant alleles, three of them (G80S, E221K, G227C) are new missense mutations located in or near the region of the active site cleft of the enzyme. The mutations co-segregate with hyperglycemia in the families of the three probands, whose biochemical and clinical phenotype is similar to other individuals with MODY 2 mutations.
 ...
PMID:Three novel missense mutations in the glucokinase gene (G80S; E221K; G227C) in Italian subjects with maturity-onset diabetes of the young (MODY). Mutations in brief no. 162. Online. 1069 20

Even in individuals who are unwilling to make prudent changes in their diets and sedentary habits, the administration of certain nutrients and/or drugs may help to prevent or postpone the onset of type 2 diabetes. The evident ability of fiber-rich cereal products to decrease diabetes risk, as documented in prospective epidemiological studies, may be mediated primarily by the superior magnesium content of such foods. High-magnesium diets have preventive (though not curative) activity in certain rodent models of diabetes; conversely, magnesium depletion provokes insulin resistance. Epidemiology also strongly suggests that regular moderate alcohol consumption has a major favorable impact on diabetes risk, particularly in women; this may reflect a direct insulin-sensitizing effect on muscle and, in women, a reduced risk for obesity. Chromium picolinate can also aid muscle insulin sensitivity, and initial reports suggest that it is an effective therapy for type 2 diabetes. High-dose biotin has shown therapeutic activity in diabetic rats and in limited clinical experience; increased expression of glucokinase in hepatocytes may mediate this benefit. Other nutrients that might prove to aid diabetic glycemic control, and thus have potential for prevention, include coenzyme Q and conjugated linoleic acids (CLA). Since the nutrients cited here - including ethanol in moderation - appear to be quite safe and (with the exception of CLA) quite affordable, supplementation with these nutrients may prove to be a practical strategy for diabetes prevention. Drugs such as metformin and troglitazone, which are expensive and require regular physician monitoring to avoid potentially dangerous side-effects, would appear to be less practical options from cost-effectiveness, convenience and safety standpoints, given the fact that the population at-risk for diabetes is huge.
 ...
PMID:Toward practical prevention of type 2 diabetes. 1085 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>