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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of hexokinase II (HKII) was examined in fat and skeletal muscle of an animal model of non-insulin-dependent diabetes mellitus, the KKAY mouse. These tissues require insulin for facilitated transport of glucose and express the insulin-responsive transporter GLUT4. The combined data from two experiments (n = 12 for each experimental condition) demonstrated mean concentrations of plasma insulin in pmol/l and glucose in mmol/l of 122 and 7.2 (control nondiabetic C57 mouse) vs. 1,118 and 29.6 (diabetic mouse), respectively. The tissues of diabetic mice compared with control mice demonstrated a reduction of HKII mRNA abundance of 68% in epididymal fat (P = 0.0001) and 34% in the quadriceps muscles (P < 0.001), with concordant reduction in the abundance of GLUT4 mRNA of 60% in epididymal fat (P < 0.001). In comparison with the results in untreated diabetic mice, diabetic animals treated with the insulin-sensitizing drug pioglitazone demonstrated an increase in the abundance of HKII mRNA with a concordant increase of GLUT4 mRNA in epididymal fat (P = 0.03 and < 0.01, respectively), and an increase of HKII mRNA in the quadriceps muscles (P < 0.05). Separate experiments demonstrated a reduction of HKII protein abundance by 61% in epididymal fat (P < 0.001, n = 12 for each experimental condition) and by 71% in the quadriceps muscles (P < 0.001, n = 6 for each experimental condition). In comparison with untreated diabetic mice, there was an increase in the abundance of HKII protein in epididymal fat of animals treated with pioglitazone (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Jan
PMID:Reduced expression of hexokinase II in insulin-resistant diabetes. 781 13

Receptors for advanced glycation end products (RAGE), which bind and internalize AGE-modified proteins formed from oxidation and other products of the nonenzymatic glycation reaction, have been mechanistically implicated in the development of the chronic complications of diabetes. In the present experiments, we sought evidence for the participation of RAGE in diabetic nephropathy by analysis of steady state levels of mRNA encoding RAGE in the renal cortex of a well-defined animal model (the db/db mouse) that develops renal pathology similar to that found in human diabetes. In these animals, increased AGE-product formation was confirmed by measurement of fluorescence in serum and renal cortex proteins. Renal involvement was confirmed by demonstration of increased urine albumin excretion and elevated serum creatinine concentrations relative to nondiabetic (db/m) littermate controls. Despite elevated concentrations of circulating and tissue AGE-modified proteins, the level of RAGE mRNA expression in renal cortex of diabetic mice did not significantly differ from that in nondiabetic littermate controls. The findings militate against changes in RAGE expression in the pathogenesis of renal abnormalities in this animal model.
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PMID:RAGE mRNA expression in the diabetic mouse kidney. 914 29

The insulin resistance of animal models of obesity (the gold thioglucose obese mouse and the o b/o b mouse) is characterized by several abnormalities. At the receptor step, both the binding function (decreased number of sites) and the enzymatic, tyrosine kinase function (decreased insulin activation) are altered. At postreceptor steps, phosphatidylinositol 3-kinase (PI3-K) plays an important role in insulin signalling, particularly for the stimulation of glucose transport in muscle and adipocyte. Insulin activation of PI3-K is markedly diminished in obese mice; starving the obese animals restores normal responses of PI3-K, glucose transport, and glycogen synthesis, to insulin. These observations emphasize the multi-site, and largely reversible, nature of insulin resistance in these animal models of obesity. Similar alterations have been reported in the literature with regard to the sites of insulin resistance in human obesity and non insulin-dependent diabetes.
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PMID:[Insulin resistance: lessons from animal models of obesity]. 922 Oct 53

Islet amyloid polypeptide forms islet amyloid deposits in non-insulin-dependent diabetes mellitus. We have generated transgenic mice which express human islet amyloid polypeptide in their pancreatic beta cells yet do not develop islet amyloid deposits despite producing levels of the amyloidogenic human peptide 2 - 3 fold higher than the native (mouse) peptide. To determine whether marked overproduction of islet amyloid polypeptide is a potential cause of islet amyloid formation, we increased expression of this transgene by producing homozygous transgenic animals and by making heterozygous mice experimentally insulin resistant with nicotinic acid. Pancreatic content of islet amyloid polypeptide-like immunoreactivity in homozygous and nicotinic acid-treated mice was 2-fold (25 +/- 7 fmol/microg; n = 6) and 3.5-fold (47 +/- 20 fmol/microg; n = 3) higher, respectively, than that of untreated heterozygous animals (13+/-2 fmol/microg; n = 11; both p < 0.05). Despite this marked increase in production of islet amyloid polypeptide, neither group of mice developed gross islet amyloid deposits even after 16 months of age. We conclude that overproduction of islet amyloid polypeptide, even as produced by extreme insulin resistance, is not in itself sufficient for islet amyloid formation.
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PMID:Transgenic overproduction of islet amyloid polypeptide (amylin) is not sufficient for islet amyloid formation. 923 Mar 54

The diabetes-susceptible class II MHC genes (in human and mouse) share unique nonaspartic acid residues at position 57 of the class II beta-chain. Transgenic expression of a mutant I-A(g7), substituting histidine and serine at position 56 and 57 of beta-chain with proline and aspartic acid (I-A(g7)PD), respectively, inhibits diabetes development in the nonobese diabetic mouse model. Here, we demonstrate that immature thymocytes expressing a diabetogenic islet Ag-specific transgenic TCR are positively selected by I-A(g7)PD class II MHC to give rise to mature CD4+ T cells. However, splenic APCs expressing the same I-A(g7)PD fail to present pancreatic islet Ag to mature T cells bearing this diabetogenic TCR. These results indicate that nonaspartic acid residues at position 57 of class II MHC beta-chain is important for diabetogenic CD4+ T cell activation in the periphery but is not essential for the formation of a diabetogenic T cell repertoire in the thymus.
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PMID:Thymic positive selection and peripheral activation of islet antigen-specific T cells: separation of two diabetogenic steps by an I-A(g7) class II MHC beta-chain mutant. 979 72

By coupling 3-(2-mercaptoethyl)quinazoline-2,4(1H,3H)dione (MECH) to divinyl sulfone activated agarose, a novel thiophilic matrix was obtained which allows the binding of immunoglobulins from different sources. In contrast to other thiophilic gels, antibodies are bound at low ionic strength and can easily be desorbed in intact form by elution with dilute alkali. The potential of using the MECH-gel was demonstrated by the purification of antibodies from human and animal (goat, rabbit, mouse) sera. The functional integrity of the purified antibodies was established with cytoplasmic islet cell antibodies from the sera of patients with type I diabetes and autoantibodies against thyroid peroxidase from patients with Graves' and Hashimoto's disease.
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PMID:A simplified procedure for the isolation of immunoglobulins from human serum using a novel type of thiophilic gel at low salt concentration. 983 92

Islet amyloid polypeptide (IAPP) is synthesized in islet beta cells and has been implicated in diabetes pathogenesis because it can inhibit insulin secretion and action and form fibrils leading to islet amyloidosis. Its physiological function has, however, not been established. We therefore examined insulin secretion and glucose elimination after i.v. or gastric gavage of glucose in transgenic mice overexpressing human IAPP (hIAPP) resulting in considerably increased circulating IAPP concentrations. The insulin response to and the glucose elimination after i.v. glucose (1 g/kg) were not different in transgenic mice compared with wild type animals, neither in males nor in females. In contrast, the insulin response to gastric glucose (150 mg/mouse) was reduced and the glucose elimination was inhibited in both male and female transgenic mice. The area under the 30 min insulin curve (AUCinsulin) was 21 +/- 2 nmol/l in 30 min in transgenic males (n = 24) vs 43 +/- 3 nmol/l in 30 min in wild type males (n = 26; p < 0.001) and the respective areas under the glucose curve (AUCglucose) were 1.90 +/- 0.12 and 1.62 +/- 0.09 mol/l in 120 min (p < 0.05). Similarly, in females, the AUCinsulin was 17 +/- 2 nmol/l in 30 min in transgenic mice vs 25 +/- 3 nmol/l in 30 min in wild type mice (p < 0.05) and the respective AUCglucose was 1.62 +/- 0.7 and 1.12 +/- 0.07 mol/l in 120 min (p < 0.001). Hence, endogenous hIAPP inhibits insulin secretion and glucose elimination after gastric glucose gavage in both male and female mice, indicating that overexpression of hIAPP could be a diabetogenic factor, via effects on the intestinal tract or the gut-islet axis or both.
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PMID:Transgenic overexpression of human islet amyloid polypeptide inhibits insulin secretion and glucose elimination after gastric glucose gavage in mice. 983 47

The electrophysiological properties of cardiac muscle in KK/Ta mouse (hereafter referred to as KK mouse), an animal model of human non-insulin-dependent diabetes mellitus, were investigated, and the findings compared with those obtained from a non-diabetic control mouse (C57BL/6J mouse; referred to as B6 mouse). The ages of the B6 mice were 23.9 +/- 5.4 weeks (n = 24) and those of the KK mice used were 25.7 +/- 10.8 weeks (n = 34). The KK mice had mild obesity, hyperglycemia and hyperinsulinemia. Ventricular muscles from both mice were examined by light microscopy. Partial myocardial fibrosis and filament disorder in the ventricular muscles were found only in the KK mice. The resting membrane potential of the ventricular muscle was less negative in the KK mice than in the control mice. The maximum rate of rise in the upstroke of the action potential was significantly decreased in the KK mice compared with that of the control mice. These suggest a decrease in a time-independent K+ current (IK1) in the KK mice. The duration of the action potential (APD) at all levels of repolarization was significantly longer in the KK mice than in the B6 mice. A blocker of transient outward current (I(to)), 4-aminopyridine, significantly prolonged the APD of the B6 mice, but failed to prolong it in the KK mice, suggesting that Ito in the diabetic mice is very small. A Ca2+ channel blocker, CoCl2, dramatically lengthened all levels of APD in both groups, suggesting that there is no difference between B6 mice and KK mice in L-type Ca2+ current via Ca2+ channels. These suggest the malfunction or deficiency of ionic channels which carry, at least Ito and IK1 in diabetic mice.
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PMID:Electrophysiological properties of ventricular muscle obtained from spontaneously diabetic mice. 1080 58

Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout (MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta-cell-specific insulin receptor knockout (betaIRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, we created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, betaIRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to betaIRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta-cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues.
Diabetes 2000 Dec
PMID:A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes. 1111 16

Sulfatide (3'sulfogalactosylceramide) is a glycosphingolipid present within the nervous system and in the islets of Langerhans. Anti-sulfatide antibodies have been observed in both pre-diabetic and newly diagnosed type 1 diabetic patients. The aim of this study was to test in vivo, the therapeutic effect of sulfatide on the development of diabetes in the NOD mouse. In four separate experiments diabetogenic splenocytes from newly diabetic NOD mice were injected iv into 7-8 week old irradiated (700R) female NOD mice (4-10 million cells/mouse). Each experiment consisted of four treatment groups to which the mice were randomly divided: 1) sulfatide; 2) galactosylceramide (the precursor to sulfatide without sulfate); 3) GM1, a glycosphingolipid negatively charged as sulfatide but with a different sugar composition; and 4) phosphate buffered saline (PBS). The mice received 100 microg glycosphingolipid iv on the day of cell transfer and 1-3 times thereafter at four day intervals, and were screened for diabetes three times a week the next 52 days. Among all the 35 sulfatide-treated mice 54% became diabetic compared to 93 % of 43 PBS-treated animals (p < 0.00001). Correspondingly, galactosylceramide reduced diabetes incidence to 52% (25 mice, p < 0.00001). On the other hand, 86% of GM1-treated mice (n=28) became diabetic indicating that no effect was obtained by this glycosphingolipid. In two experiments in which less spleen cells were transferred (4-5 mill.) and glycosphingolipids were given 4 times, 35% of the sulfatide-treated animals (n = 17) developed diabetes compared to 85% of PBS-treated mice (n = 20, p < 0.001). A robust proliferative response to sulfatide, but none to GM1, was observed when spleen cells were rechallenged with glycosphingolipid in vitro. Thus, like insulin and GAD, sulfatide is able to prevent diabetes in NOD mice.
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PMID:Treatment with sulfatide or its precursor, galactosylceramide, prevents diabetes in NOD mice. 1168 95


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