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)

Amylin, a peptide found in pancreatic amyloid deposits, may be involved in NIDDM. The effects of biosynthetic human amylin on multiple aspects of carbohydrate metabolism were studied in freshly isolated and cultured liver cells (rat hepatocytes and HepG2 cells). Acute exposure of culture liver cells to amylin had no effect on glucose incorporation into glycogen. Amylin directly reduced glucose oxidation through the hexose monophosphate shunt. The glycolytic pathway was unaffected. Amylin stimulated both glycogenolysis and gluconeogenesis. These effects were largest at amylin concentrations of 1-10 pM. Insulin partially inhibited both of these responses. Glucagon stimulated glycogenolysis and gluconeogenesis to a similar extent as amylin but required concentrations 100- to 500-fold as high. Thus, amylin, at physiologic concentrations, can impair some aspects of glucose use in liver cells and is also capable of directly stimulating glucose production, suggesting a possible involvement of amylin in the impaired glucose disposal and elevated hepatic glucose output of NIDDM.
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PMID:In vitro effects of amylin on carbohydrate metabolism in liver cells. 162 73

Recent information suggests that type 2 diabetes mellitus (NIDDM) is associated with severe insulin resistance, but other information suggests that there is a hypoinsulinemic state. To investigate the nature of the insulin resistance, 10 newly diagnosed, mildly obese type 2 diabetics and 11 long-standing type 2 diabetics with secondary failure to sulfonylureas were studied. Insulin was given by continuous subcutaneous infusion (CSII) for two weeks. CSII produced near-normoglycemia after 1-4 days in all patients with modest amounts of insulin (0.5-0.9 U/kg/24 h). These results demonstrate that whatever insulin resistance prevails in NIDDM, it does not prevent induction of normoglycemia by insulin. This suggests that either the insulin resistance is a secondary event caused by hyperglycaemia, or that NIDDM patients are hypoinsulinemic. In further studies in vitro, the effect of glucose on the rate of glycolytic glucose utilization by isolated rat soleus muscle and on hexose transport in rat skeletal myocyte line L8 were assessed. In the first case, an increase in glucose concentration led to a decrease in muscle glycolysis, and in the second case a hyperglycemic concentration of glucose led to a marked reduction in hexose transport, which was fully reversible within two hours. The clinical and in vitro results plus literature data suggest that insulin resistance can be overcome by insulin in NIDDM, and that beta-cell responsiveness to glucose is greatly reduced in NIDDM, but the defect is restricted to the acute stimulatory phase of glucose induction of insulin release. If this defect can be corrected, acute insulin release will occur so that NIDDM would be cured notwithstanding the existence of insulin resistance.
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PMID:Insulin resistance, insulin deficiency, and non-insulin-dependent diabetes mellitus. 179 64

During hyperinsulinemic glucose-clamp studies, intravenous infusion of calcitonin gene-related peptide (CGRP) in rats antagonized the ability of insulin to stimulate peripheral glucose disposal by 52% (196 +/- 7.2 vs. 105 +/- 10.5 mumol.kg-1.min-1, P less than 0.05) and to inhibit hepatic glucose output by 54% (P less than 0.01). CGRP also inhibited the in vitro effects of insulin to stimulate hexose uptake in cultured BC3H1 myocytes at all insulin concentrations studied. Amylin is a peptide isolated from amyloid deposits in pancreatic islets of type II (non-insulin-dependent) diabetic subjects, is present in normal beta-cells, and bears a striking homology to CGRP. When synthetic human amylin was infused during clamp studies, it inhibited the ability of insulin to stimulate glucose disposal by 56% (96.9 +/- 9.4 vs. 42.4 +/- 5.0 mumol.kg-1.min-1, P less than 0.05) and to suppress hepatic glucose output by 64%. Therefore, amylin and CGRP can cause insulin resistance in vivo and may be implicated in insulin-resistant states such as type II diabetes mellitus.
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PMID:Induction of insulin resistance in vivo by amylin and calcitonin gene-related peptide. 222 35

Non-insulin-dependent diabetes (NIDDM) was obtained in adult rats following a neonatal streptozotocin injection. Rats with NIDDM exhibited slightly lowered plasma insulin, slightly elevated basal plasma glucose values (less than 200 mg/dl), and low pancreatic insulin stores (50% of the controls). Insulin secretion was studied in this model using the isolated perfused pancreas technique. Insulin response to glucose stimulation over the range 5.5-22 mM was lacking, thus indicating complete loss of B-cell sensitivity to glucose. Even in presence of theophylline, the B-cells remained insensitive to glucose. In contrast, glyceraldehyde elicited an insulin release as important as that obtained in the control pancreata. This could possibly suggest that the B-cell dysfunction in rats with NIDDM involves a block in glucose metabolism in the early steps of glycolysis prior to the triose-phosphate. Mannose stimulated insulin secretion less in the diabetics than in the controls. The insulin secretion obtained in response to isoproterenol indicated that the ability of the adenylcyclase to generate cAMP in the B-cells of the diabetics was not decreased. The insulinotropic actions of acetylcholine and tolbutamide were normal and increased, respectively, as compared with the controls. In the absence of glucose, the B-cells of the diabetics were unexpectedly hypersensitive to arginine and leucine. The alpha-ketoisocaproate effect in the diabetics was not significantly different from that obtained in the controls. The possibility that enhancement of insulin response to leucine in the diabetics might be related to a more active conversion of leucine to ketoisocaproate along the first steps of intraislet leucine metabolism is proposed.
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PMID:Glucose insensitivity and amino-acid hypersensitivity of insulin release in rats with non-insulin-dependent diabetes. A study with the perfused pancreas. 634 Nov 28

A decreased insulin response, preferentially to glucose, has been considered a hallmark of non-insulin dependent diabetes mellitus (Type 2) in humans. Syndromes resembling human diabetes occur spontaneously in many animal species and can also be induced by treating animals with drugs or viruses, excising their pancreases or manipulating their diet. Among these models, rat diabetes induced by neonatal streptozotocin administration (n-STZ models) has been first recognized as an adequate tool to study the long-term consequences of a gradually reduced beta-cell mass. More recently, the GK (Goto Kakisaki) Wistar rat has become available and is now considered as a promising spontaneous rat model of non-insulin dependent diabetes. We and others have found that defects in insulin secretion and action develop in the n-STZ and the GK models, which in many ways resemble those described in human non-insulin dependent diabetes. This review is aimed to sum up with a comparative approach, the informations so far collected in the n-STZ and GK models concerning the cellular mechanisms leading to the desensitization of their beta-cells to glucose. Taken together, the data reinforce the view that the impairment of glucose-induced insulin release in n-STZ and GK rats is clearly related to a defect in oxidative glycolysis. This leads to a severe decrease in the mitochondrial oxidative catabolism of glucose-derived pyruvate. Its coincides with a lower ATP/ADP ratio in glucose-stimulated islets and a subsequent alteration of ionic events tightly coupled to the fuel function of the hexose in islet cells, i.e. the decrease in K+ conductance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose refractoriness of pancreatic beta-cells in rat models of non-insulin dependent diabetes. 780 48

Succinic acid esters are currently under investigation as possible insulinotropic tools in the treatment of noninsulin-dependent diabetes mellitus. The present article introduces three novel nutrient esters and aims mainly to explore, in both normal and GK rats, the secretory response to such esters when tested alone or in combination. It documents that in pancreatic islets from normal rats, methyl acetate (10 mM), which fails to augment basal insulin output, potentiates the secretory response to succinate dimethyl ester (also 10 mM). It also reveals that alpha-D-glucose pentaacetate (alpha GPA) (1.7 mM) stimulates insulin release in the absence of any other exogenous nutrient and even more so in the presence of succinate methyl ester. Moreover, the methyl esters of succinic acid (10 mM), when used together with either methyl acetate or alpha GPA, provoked insulin secretion in islets from diabetic GK rats incubated in the absence of D-glucose, although no significant secretory response of such islets could be detected when each of these agents was tested separately. These findings thus draw attention to the insulinotropic potential in type 2 diabetes of selected combinations of nutrient esters, including a D-glucose ester presumably able to enter into islet cells without requiring the intervention of a hexose carrier.
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PMID:Synergistic insulinotropic action of succinate, acetate, and glucose esters in islets from normal and diabetic rats. 954 40

Apoptosis of retinal capillary cells begins early in diabetes and likely contributes to the capillary obliteration that is an important feature of diabetic retinopathy. Caspases are proteolytic enzymes that are closely involved in the induction and execution phases of apoptosis, but their role in the development of diabetic retinopathy has not been studied previously. Our study focused on the measurement of activities of multiple caspases in retinas of mice at different durations of diabetes. Several caspases (including caspases-1, -2, -6, -8, and -9) were activated as early as 2 months of diabetes. The caspases activity pattern changed with increasing duration of disease, suggesting a slowly developing caspases cascade. Activities of executioner caspases (e.g., cas-6 and -3) became elevated after longer duration of diabetes, and the induction of cas-3 activity was associated with the duration of diabetes at which capillary cells begin to show evidence of undergoing apoptosis. Retinas from patients with type 2 diabetes likewise showed a significant increase in activities of cas-1, -3, -4, and -6. For comparison, retinal caspases were also measured in experimental galactosemia, another model that develops a diabetic-like retinopathy. The pattern of caspases activation differed between diabetes and galactosemia, but cas-1 activity became elevated soon after elevation of blood hexose concentration in both. Caspases offer new therapeutic targets to test the role of apoptosis in the development of diabetic retinopathy.
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PMID:Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients. 1191 41

This review focuses on the link between diabetes mellitus and oxidative stress and, in particular, on the role that moderate wine consumption may play in preventing diabetic complications and the onset of diabetes. With this aim, a search of PubMed was carried out for literature published up to March 2003. In diabetes mellitus, oxidative stress results both from exposure to hyperglycaemia through glycoxidation and sorbitol system activation, and from functional limitation of the hexose monophosphate shunt, leading to a decrease in glutathione synthesis. Oxidative stress alters the plasma lipoprotein profile (particularly low-density lipoproteins), the coagulative parameters (with an increased thrombotic risk), the endothelium (with a decrease in prostacyclin synthesis and an increase of thromboxane production) and the cell membranes (which undergo peroxidation). In diabetic patients, an altered oxidative pattern is present not only in the fasting state but also especially after food intake. In particular, food intake induces a decrease in the total radical-trapping antioxidant parameter (TRAP) and an elevation of hydroperoxides and thiobarbituric acid reactive substances (TBARS). Previously several clinical trials tried to improve the diabetic oxidative status using alpha-tocopherol, ascorbic acid and beta-carotene supplementation. Some authors found, in normal subjects, a reduction of hydroperoxides postprandially when the meal included red wine. Other authors showed that the oxidative pattern present in type 2 diabetic patients was mitigated by red wine. These actions may reduce cardiovascular risk. Moreover, an inverse relationship was observed between alcohol consumption and the incidence of type 2 diabetes; this relationship was valid for a light to moderate intake and it seemed to depend on drinking regularly and to be independent of the type of alcoholic beverage. In conclusion, moderate and regular wine consumption could ameliorate the diabetic oxidative status. This lifestyle measure might contribute to preventing diabetic complications and the onset of diabetes.
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PMID:Diabetes mellitus: oxidative stress and wine. 1460 79

Type 2 diabetes is a complex disorder with diminished insulin secretion and insulin action contributing to the hyperglycemia and wide range of metabolic defects that underlie the disease. The contribution of glucose metabolic pathways per se in the pathogenesis of the disease remains unclear. The cellular fate of glucose begins with glucose transport and phosphorylation. Subsequent pathways of glucose utilization include aerobic and anaerobic glycolysis, glycogen formation, and conversion to other intermediates in the hexose phosphate or hexosamine biosynthesis pathways. Abnormalities in each pathway may occur in diabetic subjects; however, it is unclear whether perturbations in these may lead to diabetes or are a consequence of the multiple metabolic abnormalities found in the disease. This review is focused on the cellular fate of glucose and relevance to human type 2 diabetes.
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PMID:The cellular fate of glucose and its relevance in type 2 diabetes. 1546 41

D-mannose is an essential monosaccharide constituent of glycoproteins and glycolipids. However, it is unknown how plasma mannose is supplied. The aim of this study was to explore the source of plasma mannose. Oral administration of glucose resulted in a significant decrease of plasma mannose concentration after 20 min in fasted normal rats. However, in fasted type 2 diabetes model rats, plasma mannose concentrations that were higher compared with normal rats did not change after the administration of glucose. When insulin was administered intravenously to fed rats, it took longer for plasma mannose concentrations to decrease significantly in diabetic rats than in normal rats (20 and 5 min, respectively). Intravenous administration of epinephrine to fed normal rats increased the plasma mannose concentration, but this effect was negated by fasting or by administration of a glycogen phosphorylase inhibitor. Epinephrine increased mannose output from the perfused liver of fed rats, but this effect was negated in the presence of a glucose-6-phosphatase inhibitor. Epinephrine also increased the hepatic levels of hexose 6-phosphates, including mannose 6-phosphate. When either lactate alone or lactate plus alanine were administered as gluconeogenic substrates to fasted rats, the concentration of plasma mannose did not increase. When lactate was used to perfuse the liver of fasted rats, a decrease, rather than an increase, in mannose output was observed. These findings indicate that hepatic glycogen is a source of plasma mannose.
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PMID:Hepatic glycogen breakdown is implicated in the maintenance of plasma mannose concentration. 1553 4


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