Disease relevance of Niddm1

• Non-insulin dependent diabetes mellitus (NIDDM) is a major public health problem, but its aetiology remains poorly understood [1].
• Neural disturbances are observed in the peripheral and central nervous systems of patients with insulin-dependent diabetes mellitus (IDDM) and non-IDDM (NIDDM) [2].
• This feedback mechanism may be important in the local integration of hormonal signals which regulate insulin secretion and in alterations of metabolic homeostasis associated with obesity and non-insulin dependent diabetes mellitus (NIDDM) [3].
• Spontaneous and dexamethasone-induced noninsulin-dependent diabetes mellitus (NIDDM) in rats is associated with loss of glucose-stimulated insulin secretion (GSIS) and a reduction in both GLUT-2-positive beta cells and high Km glucose transport [4].
• Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks [5].

Psychiatry related information on Niddm1

• Epidemiological studies suggest that alcohol consumption is an independent risk factor for the development of non-insulin-dependent diabetes mellitus (NIDDM) [6].
• CONCLUSIONS: The results indicate that impaired glucose metabolism may influence one of the defense mechanisms for oxidative stress, but also suggest that decreased glutathione levels occur prior to morphological signs of pericyte loss and/or endothelial cell proliferation in this animal model of hereditary NIDDM [7].
• NIDDM causes erectile dysfunction, which slowly progresses [8].

High impact information on Niddm1

• Glucagon-like-peptide-1(7-37) (GLP-1) is an intestinally derived hormone that may be useful for the treatment of NIDDM because it acts in vivo to increase the level of circulating insulin, and thus lower the concentration of blood glucose [9].
• Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a disorder of glucose homeostasis characterized by hyperglycaemia, peripheral insulin resistance, impaired hepatic glucose metabolism, and diminished glucose-dependent secretion of insulin from pancreatic beta-cells [9].
• Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM) [10].
• To determine if the chronology and correlation of these abnormalities is consistent with a causal relationship, Zucker (fa/fa) rats were studied longitudinally before and during 10 d of dexamethasone-induced (0.4 mg/kg per d i.p.) NIDDM [4].
• The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS [5].

Chemical compound and disease context of Niddm1

• In order to examine the possible impairment of KATP channel function in non-insulin-dependent diabetes mellitus (NIDDM), we have studied the properties of the KATP channels in single beta cells of neonatally streptozotocin-induced diabetic rats (NSZ rats) using the patch-clamp technique [11].
• Non-insulin-dependent diabetes mellitus (NIDDM) was obtained in adult female rats by neonatal administration of streptozocin (STZ) [12].
• Troglitazone is an orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and NIDDM subjects [13].
• A new oral agent, 5-[4-(2-(5-ethyl 12-pyridyl)ethoxy]- benzoyl]-2,4-thiazolidinedione (pioglitazone), has been developed for treatment of non-insulin-dependent diabetes mellitus (NIDDM) [14].
• We have proposed that chronic hyperglycemia causes the abnormal glucose influence on arginine-stimulated insulin secretion in the neonatal streptozocin (STZ) rat model of NIDDM and therefore studied the effect of 24 h of mild insulin-induced hypoglycemia on this defect [15].

Biological context of Niddm1

• Congenic strains have been established for the major diabetes locus, Niddm1, by transfer of GK alleles onto the genome of the normoglycemic F344 rat [16].
• Niddm1 was dissected into two subloci, physically separated in the congenic strains Niddm1b and Niddm1i, each with at least one disease susceptibility gene [16].
• Despite the polygenic nature of diabetes in GK, the locus-specific diabetes phenotype was retained in the congenic strain Niddmla, containing a GK-derived genomic fragment of 52 cM from the Niddm1 locus [17].
• The major diabetes quantitative trait locus (Niddm1), which segregates in crosses between GK rats affected with spontaneous type 2-like diabetes and normoglycemic F344 rats, encodes at least two different diabetes susceptibility genes [18].
• Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM) [5].

Anatomical context of Niddm1

• In addition, IGF-I mRNA content was reduced in liver but not nerve or spinal cord of NIDDM rats [2].
• Obese subjects, especially those with visceral fat accumulation, are frequently associated with hyperlipidemia, non-insulin-dependent diabetes mellitus (NIDDM), and hypertension [19].
• Insulin production and glucose metabolism in isolated pancreatic islets of rats with NIDDM [20].
• Because skeletal muscle plays a major role in glucose disposal, it may be the primary site of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) [21].
• In NIDDM, B-cells are insensitive to glucose [22].

Associations of Niddm1 with chemical compounds

• Congenic strains were established for Niddm1, the major quantitative trait locus (QTL) for postprandial glucose levels, by transfer of GK alleles onto the genome of the normoglycemic F344 rat [17].
• Non-insulin-dependent diabetes (NIDDM) was obtained in adult rats following a neonatal streptozotocin injection [23].
• Studies were performed to test the hypothesis that impaired insulin action occurs as an acquired phenomenon in the streptozocin (STZ)-treated, non-insulin-dependent (NIDDM) diabetic rat model [24].
• The onset of NIDDM in obese Zucker diabetic fatty (fa/fa) rats is preceded by a striking increase in the plasma levels of free fatty acids (FFAs) and by a sixfold rise in triglyceride content in the pancreatic islets [25].
• These results suggested that pioglitazone increased insulin sensitivity in part by activating kinase of the receptors through indirect effect on insulin receptors and that the drug may have useful benefits in insulin resistance of NIDDM [14].

Regulatory relationships of Niddm1

• Plasma glucagon responses to insulin-induced hypoglycemia and arginine in spontaneous non-insulin-dependent diabetes mellitus (NIDDM) rats, Otsuka Long Evans Tokushima Fatty (OLETF) strain [26].

Other interactions of Niddm1

• Since UCP-3 mRNA levels are reduced in skeletal muscle of diabetic patients, this effect may be involved in the improvement of insulin sensitivity caused by bezafibrate in NIDDM [27].
• These results suggest that insulin resistance in OLETF rats, a spontaneous NIDDM model rat, may be associated with deterioration of insulin-induced DG-PKC signaling and subsequent decrease in PI 3-kinase activation [28].
• Recent advances in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) include the use of thiazolidinediones (TZDs), agents that enhance insulin action, in part, through an activation of adipose tissue peroxisome proliferator-activated receptor gamma [29].
• Islet amyloid polypeptide (IAPP) has been identified as the major constituent of the pancreatic amyloid of non-insulin-dependent diabetes mellitus (NIDDM) and is also present in normal beta-cell secretory granules [30].
• If TNF-alpha plays a role in the development of the obesity/NIDDM syndrome, troglitazone may prove useful in its treatment [31].

Analytical, diagnostic and therapeutic context of Niddm1

• We have performed a comprehensive study of the genetic basis of diabetes in the Goto-Kakizaki (GK) rat, the most widely used animal model of non-obese NIDDM [1].
• The genetic dissection of NIDDM using this model has allowed us to map three independent loci involved in the disease [1].
• We have examined the effect of chronic (20 days) oral administration of benfluorex (35 mg/kg) in a rat model of NIDDM, induced by injection of STZ 5 days after birth and characterized by frank hyperglycemia, hypoinsulinemia, and hepatic and peripheral insulin resistance [32].
• The unitary conductance of the channel in diabetic beta-cells was virtually identical to that in control beta cells and there was no difference in the sensitivity to ATP and glibenclamide of KATP channels between the NIDDM and control groups [11].
• We have used the whole-cell recording technique to determine whether ATP-sensitive potassium (K[ATP]) currents, voltage-dependent Ca2+ currents, and exocytosis are different in single beta-cells from pancreatic islets of Goto-Kakizaki (GK) rats, a novel model of NIDDM, and normal rats [33].

References