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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of the many information obtainable from the urine of diabetic patients, urinary C-peptide (CPR), albumin and anti-diuretic hormone (ADH) were representatively described using my clinical and experimental data. C-peptide excretion in 24h collection of urine is a good estimate of insulin secretion from the pancreas and thus low in IDDM patients and even in NIDDM patients at a later stage, but high in pathological conditions including Graves' disease, obesity, liver cirrhosis and Cushing's syndrome. Urinary albumin excretion in small amounts (microalbuminuria) is usually observed in diabetic patients who have been under a poor control state of diabetic hyperglycemia for over 5 years and provides a good tool for monitoring early diabetic nephropathy. The grade of microalbuminuria (30-300 mg/day) is positively correlated with the HbA1 level in diabetic patients, showing that microalbuminuria is reversible along with an improvement of diabetic control at least in an early phase of diabetic nephropathy. As the albumin level measured in a spot urine sample correlates well with the value in the 24h collection of urine, the albumin measurement is conveniently feasible with a spot urine sample at every patient's visit. The amount of ADH excreted in urine is 7-10% of that secreted from the posterior pituitary. The excretion of ADH in a day was in the urine of diabetic patients positively correlated with HbA1, urinary osmolarity and concentration of sodium in urine, although the pathological meaning of the observed ADH hypersecretion in the development of diabetic complications is currently unknown.
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PMID:[Pathophysiological analysis of diabetes mellitus and complications from the urine of diabetic patients]. 150 92

The role of fat in the aetiology of insulin resistance and type 2 diabetes has been re-considered in the present review. This is because of the questions raised by recent created mouse models imitating human lipodystrophy diabetes. It appears that hepatic steatosis, which is shared by both lipodystrophy and most if not all obesity patients, may play a key role in the pathogenesis of insulin resistance and type 2 diabetes despite the fact that lipodystrophy is an extreme state and occurs more rarely than obesity. The possible link between lipid and glucose metabolisms via peroxisome activity has been examined and its role in determining hyperglycaemia is suggested. Moreover, new avenues towards a better understanding of insulin resistance at the genomic level have also been proposed. It appears that one of the most fundamental biological phenomena, fuel selection, may underlie the causes of diabetic hyperglycaemia and perplex the role of fat in the aetiology of insulin resistance.
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PMID:The role of increased liver triglyceride content: a culprit of diabetic hyperglycaemia? 1192 13

Increasing evidence shows that the overproduction of reactive oxygen species, induced by diabetic hyperglycemia, contributes to the development of several cardiopathologies. The susceptibility of diabetic hearts to oxidative stress, induced in vitro by ADP-Fe2+ in mitochondria, was studied in 12-month-old Goto-Kakizaki rats, a model of non-insulin dependent diabetes mellitus, and normal (non-diabetic) Wistar rats. In terms of lipid peroxidation the oxidative damage was evaluated on heart mitochondria by measuring both the O2 consumption and the concentrations of thiobarbituric acid reactive substances. Diabetic rats display a more intense formation of thiobarbituric acid reactive substances and a higher O2 consumption than non-diabetic rats. The oxidative damage, assessed by electron microscopy, was followed by an extensive effect on the volume of diabetic heart mitochondria, as compared with control heart mitochondria. An increase in the susceptibility of diabetic heart mitochondria to oxidative stress can be explained by reduced levels of endogenous antioxidants, so we proceeded in determining alpha-tocopherol, GSH and coenzyme Q content. Although no difference of alpha-tocopherol levels was found in diabetic rats as compared with control rat mitochondria, a significant reduction in GSH (21.5% reduction in diabetic rats) and coenzyme Q levels of diabetic rats was observed. The data suggest that a significant decrease of coenzyme Q9, a potent antioxidant involved in the elimination of mitochondria-generated reactive oxygen species, may be responsible for an increased susceptibility of diabetic heart mitochondria to oxidative damage.
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PMID:Diabetes and mitochondrial oxidative stress: a study using heart mitochondria from the diabetic Goto-Kakizaki rat. 1284 58

Complex though integrated hormonal and metabolic changes characterize pregnancy. In the face of progressive decline in insulin action, glucose homeostasis is maintained through a compensatory increase in insulin secretion. This switches energy production from carbohydrates to lipids, making glucose readily available to the fetus. This precise and entangled hormonal and metabolic condition can, however, be disrupted and diabetic hyperglycemia can develop (gestational diabetes). The increase in plasma glucose level is believed to confer significant risk of complications to both the mother and the fetus and the newborn. Moreover, exposition of fetal tissues to the diabetic maternal environment can translate into an increased risk for development of diabetes and/or the metabolic syndrome in the adult life. In women with previous gestational diabetes, the risk of developing type 2 diabetes is greatly enhanced, to the point that GDM represents an early stage in the natural history of type 2 diabetes. In these women, accurate follow-up and prevention strategies are needed to reduce the subsequent development of overt diabetes. This paper will review current knowledge on the modifications occurring in normal pregnancy, while outlining the mechanisms. In this paper, we will review the changes of intermediary metabolism occurring during pregnancy. In particular, we will outline the mechanisms responsible for gestational diabetes; the link between these alterations and associated maternal and neonatal morbidity will be examined.
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PMID:Intermediate metabolism in normal pregnancy and in gestational diabetes. 1287 3

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
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PMID:Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists. 1511 85

The nature of the progressive beta-cell failure occurring as normal glucose tolerant (NGT) individuals progress to type 2 diabetes (T2DM) is incompletely understood. We measured insulin sensitivity (by a euglycemic insulin clamp) and insulin secretion rate (by deconvolution of plasma C-peptide levels during an oral glucose tolerance test) in 188 subjects [19 lean NGT (body mass index [BMI] </= 25 kg/m(2)), 42 obese NGT, 22 BMI-matched impaired glucose tolerance [IGT], and 105 BMI-matched T2DM]. Main determinants of beta-cell function on the oral glucose tolerance test were derived from a mathematical model featuring the following: 1) glucose concentration-insulin secretion dose response (glucose sensitivity), 2) a secretion component proportional to the derivative of plasma glucose concentration (rate sensitivity); and 3) a potentiation factor. When NGT and T2DM were subgrouped by 2-h plasma glucose concentrations, insulin secretion rate revealed an inverted U-shaped pattern, rising through NGT up to IGT and falling off thereafter. In contrast, beta-cell glucose sensitivity dropped in a monophasic, curvilinear fashion throughout the range of 2-h plasma glucose. Within the NGT range (2-h glucose of 4.1-7.7 mmol/liter), beta-cell glucose sensitivity declined by 50-70% (P < 0.02). Insulin sensitivity decreased sharply in the transition from lean to obese NGT and then declined further in IGT and mild T2DM to level off in the higher three quartiles of diabetic hyperglycemia. In T2DM, defective beta-cell potentiation and rate sensitivity also emerged (P </= 0.05). In the whole data set, insulin sensitivity and the dynamic parameters of beta-cell function explained 89% of the variability of 2-h plasma glucose levels. The following conclusions were reached: 1) beta-cell glucose sensitivity falls already within the NGT range in association with rising 2-h plasma glucose concentrations, although absolute insulin secretion rates increase; and 2) throughout the glucose tolerance range, dynamic parameters of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) and insulin sensitivity are independent determinants of 2-h plasma glucose levels.
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PMID:beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. 1548 86

Obesity is the driving force behind the worldwide increase in the prevalence of type 2 diabetes mellitus. Hyperglycaemia is a hallmark of diabetes and is largely due to increased hepatic gluconeogenesis. The medial hypothalamus is a major integrator of nutritional and hormonal signals, which play pivotal roles not only in the regulation of energy balance but also in the modulation of liver glucose output. Bidirectional changes in hypothalamic insulin signalling therefore result in parallel changes in both energy balance and glucose metabolism. Here we show that activation of ATP-sensitive potassium (K(ATP)) channels in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. Finally, the infusion of a K(ATP) blocker within the mediobasal hypothalamus, or the surgical resection of the hepatic branch of the vagus nerve, negates the effects of central insulin and halves the effects of systemic insulin on hepatic glucose production. Consistent with these results, mice lacking the SUR1 subunit of the K(ATP) channel are resistant to the inhibitory action of insulin on gluconeogenesis. These findings suggest that activation of hypothalamic K(ATP) channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia.
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PMID:Hypothalamic K(ATP) channels control hepatic glucose production. 1584 27

The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
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PMID:Design and synthesis of dual peroxisome proliferator-activated receptors gamma and delta agonists as novel euglycemic agents with a reduced weight gain profile. 1697 Mar 91

Inappropriate adaptation of beta-cell mass is a primary cause of the development of diabetic hyperglycemia. However, the mechanisms underlying regulation of the beta-cell mass in response to insulin resistance or in the development of type 2 diabetes remain unclear. We determined the insulin signaling in the beta-cells and the adaptation of the beta-cell mass in response to the progression of insulin resistance in OLETF rats. By 25 weeks of age, at the onset of diabetes, compared to control LETO rats, OLETF rats developed obesity (Body weight: LETO vs OLETF = 474.0+/-9.5 vs 581.3+/-21.8 g, P < 0.001, n=6), hyperlipidemia (Cholesterol: LETO vs OLETF = 1.67+/-0.07 vs 2.19+/-0.20 mM, P < 0.05, n=6; triglyceride: LETO vs OLETF = 0.36+/-0.05 vs 1.36+/-0.12 mM, P < 0.001, n=6), and impaired glucose tolerance (AUC: LETO vs OLETF = 10.3+/-3.4 vs 29.6+/-7.8 mM, P < 0.001, n=6). Insulin sensitivities as assessed by the insulin sensitivity index (ISI) and the homeostasis model assessment (HOMA) indicated that OLETF rats developed severe insulin resistance. The measurement of plasma insulin levels by ELISA demonstrated, at the onset of diabetes, that fasting insulin levels were increased by 1.2-fold, and 2 hr postprandial insulin levels were increased by 3-fold (P < 0.05, n=6) in OLETF rats compared to age-matched LETO mates which is suggestive of hyperinsulinemia. Immunostaining detected a significant reduction in the insulin receptor substrate 1 (IRS1) (by 54%, P < 0.001) and IRS2 (by 55%, P < 0.001) in the beta-cells of the OLETF rats. Interestingly, while the beta-cell mass was found to be increased (by 2.2-fold; P < 0.001), the beta-cell insulin content as determined by immunostaining was significantly reduced by 32% (P < 0.001) in the OLETF rats when compared to the controls. Our findings suggest that despite increasing beta-cell mass the impaired beta-cell insulin signaling and reduced beta-cell insulin content may contribute to the onset of overt diabetes in OLETF rats.
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PMID:Increased beta-cell apoptosis and impaired insulin signaling pathway contributes to the onset of diabetes in OLETF rats. 1845 52

Uncontrolled hepatic glucose output (HGO) contributes significantly to the pathological hyperglycemic state of patients with type 2 diabetes. Glucagon, through action on its receptor, stimulates HGO, thereby leading to increased glycemia. Antagonizing the glucagon signaling pathway represents an attractive therapeutic approach for the treatment of type 2 diabetes. We previously reported the generation and characterization of several high-affinity monoclonal antibodies (mAbs) targeting the glucagon receptor (GCGR). In the present study, we demonstrate that a 5-week treatment of diet-induced obese mice with mAb effectively normalized nonfasting blood glucose. Similar treatment also reduced fasting blood glucose without inducing hypoglycemia or other undesirable metabolic perturbations. In addition, no hypoglycemia was found in db/db mice that were treated with a combination of insulin and mAb. Long-term treatment with the mAb caused dose-dependent hyperglucagonemia and minimal to mild alpha-cell hyperplasia in lean mice. There was no evidence of pancreatic alpha-cell neoplastic transformation in mice treated with mAb for as long as 18 weeks. Treatment-induced hyperglucagonemia and alpha-cell hyperplasia were reversible after treatment withdrawal for periods of 4 and 10 weeks, respectively. It is noteworthy that pancreatic beta-cell function was preserved, as demonstrated by improved glucose tolerance throughout the 18-week treatment period. Our studies further support the concept that long-term inhibition of GCGR signaling by a mAb could be an effective approach for controlling diabetic hyperglycemia.
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PMID:Long-term inhibition of the glucagon receptor with a monoclonal antibody in mice causes sustained improvement in glycemic control, with reversible alpha-cell hyperplasia and hyperglucagonemia. 1972 Aug 78


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