UMLS:C0011860 - FACTA Search

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

Calcium- and phospholipid-dependent protein kinase (protein kinase C; PKC) may be an important mediator in transduction of some of the cellular actions of insulin. We studied PKC activity in freshly isolated circulating mononuclear cells obtained from healthy subjects and patients with non-insulin-dependent (type II) diabetes mellitus (NIDDM). The kinase activity was measured using a specific nonapeptide substrate, Ala-Ala-Ala-Ser-Phe-Lys-Ala-Lys-Lys-amide. There was negligible calcium- and phospholipid-independent kinase activity in cytosolic and particulate fractions of cells from both control and diabetic subjects. Total (cytosolic and particulate) PKC activity of mononuclear cells from poorly controlled diabetic patients was significantly reduced compared with controls; this reduction was mainly due to a decrease in the cytosolic kinase activity. Tumor-promoting phorbol ester (TPA, 0.1 mumol/L) induced translocation of PKC activity in control cells; in contrast, this subcellular redistribution was not observed in cells from a majority of poorly controlled diabetic subjects. Increased calcium influx into the cells caused by the calcium ionophore A23187-triggered translocation of PKC activity in control cells, while it was ineffective in cells from poorly controlled diabetic patients. Cells from well-controlled diabetic patients demonstrated TPA-induced translocation of the PKC activity approaching that of control cells. The total PKC activity in cells from patients with good glycemic control was normal. Impaired activation of PKC is thus associated with the insulin resistance found in patients with poorly controlled NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired translocation of protein kinase C activity in human non-insulin-dependent diabetes mellitus. 186 31

Insulin resistance of the skeletal muscle plays a key role in the development of the metabolic endocrine syndrome and its further progression to non-insulin dependent diabetes (NIDDM). Available data suggest that insulin resistance is caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. The impaired response of the insulin receptor tyrosine kinase which is found in NIDDM appears to contribute to the pathogenesis of the signalling defect. The reduced kinase activation is not caused by mutations within the insulin receptor gene. We investigated two potential mechanisms that might be relevant for the abnormal function of the insulin receptor in NIDDM, i.e. changes in the expression of the receptor isoforms and the effect of hyperglycaemia on insulin receptor tyrosine kinase activity. The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). We found that HIR-B expression in the skeletal muscle is increased in NIDDM. However, the characterisation of the functional properties of HIR-A and HIR-B revealed no difference in their tyrosine kinase activity in vivo. The increased expression of HIR-B might represent a compensatory event. In contrast, hyperglycaemia might directly inhibit insulin-receptor function. We have found that in rat-1 fibroblasts which overexpressing human insulin receptor an inhibition of the tyrosine kinase activity of the receptor may be induced by high glucose levels. This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation. 782 30

The plasma membrane enzyme (Ca2+ + Mg2+)-adenosine triphosphatase (ATPase) is hormonally regulated and may participate in Ca2+ signaling by removing excess Ca2+ from the cell. Therefore, observations of a hormone-specific loss of insulin stimulation of ATPase in kidney membranes from non-insulin-dependent diabetic (NIDDM) rats may reflect their insulin-resistant state. Consequently, to evaluate whether additional insulin-resistant conditions are associated with impaired function of ATPase and with loss of regulation of the enzyme by insulin, studies were extended to investigate (Ca2+ + Mg2+)-ATPase activities and hormonal regulation of the enzyme in kidney basolateral membranes from obese and lean Zucker rats. (Ca2+ + Mg2+)-ATPase activity was lower in membranes from obese rats compared with lean rats. Maximal velocity (Vmax) of the enzyme activity was 29.2 +/- 2.6 nmol Pi/mg/min in obese rats versus 57.2 +/- 6.5 in lean rats (P < .05). However, the affinity of the enzyme for Ca2+ was similar in obese and lean rats (Km Ca2+, 0.23 +/- 0.025 v 0.23 +/- 0.032 mumol/L Ca2+). Also, the Km for ATP of the enzyme was similar in membranes from obese and lean rats. Insulin, parathyroid hormone (PTH), and cyclic adenosine monophosphate (cAMP) stimulated the ATPase activity in membranes from lean rats in a dose-dependent manner (15% to 28%). Also, the protein kinase C (PKC) stimulator 12-O-tetradecanoyl phorbol-13-acetate (TPA) increased the ATPase activity in membranes from lean rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased activity of (Ca2+ + Mg2+)-adenosine triphosphatase (ATPase) and a hormone-specific defect in insulin regulation of ATPase in kidney basolateral membranes from obese fa/fa rats. 805 47

The plasma membrane enzyme (Ca2+ + Mg2+)-adenosine triphosphatase [(Ca2+ + Mg2+)-ATPase] is hormonally regulated, and may participate in Ca2+ signaling by removing excess Ca2+ from the cell. Insulin increases ATPase activity in kidney cortical basolateral membranes (BLM) from normal rats, but fails to do so in membranes from insulin-resistant non-insulin-dependent diabetic (NIDDM) rats. To investigate mechanisms of insulin regulation of ATPase and to evaluate whether the loss of this regulation in diabetes is hormone-specific and depends on blood glucose levels, (Ca2+ + Mg2+)-ATPase function and its hormonal regulation were studied in kidney BLM from rats with mild and severe NIDDM. Km values for ATP and Ca2+ affinity of the ATPase were similar in diabetic and control rats, but the maximal velocity (Vmax) of the enzyme was higher in diabetic groups. Insulin, the protein kinase C (PKC) stimulator 12-0-tetradecanoylphorbol 13-acetate (TPA), parathyroid hormone (PTH), and cyclic adenosine monophosphate (cAMP) all increased the ATPase activity in BLM from controls by increasing the enzyme's affinity for Ca2+. A protein kinase A (PKA) inhibitor (H8 in low concentrations) abolished cAMP and PTH effects, but not those of insulin, whereas the PKC inhibitors (sphingosine and high concentrations of H8) did abolish the effects of insulin. Stimulations of ATPase activity by insulin and by PTH and cAMP were additive. Insulin and TPA lost their stimulatory effects on ATPase in BLM from rats with either mild or severe NIDDM, but PTH and cAMP maintained their stimulatory effects in these membranes. The data show [1] (Ca2+ + Mg2+)-ATPase activity is increased in NIDDM, and a hormone-specific loss of insulin stimulation of ATPase occurs; (2) these defects are not dependent on the level of glycemia; and (3) the stimulatory effects of insulin on the ATPase may be mediated in part via PKC. We suggest that the hormone-specific defect in insulin regulation of ATPase seen in the NIDDM rats may contribute to their insulin resistance.
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PMID:Hormone-specific defect in insulin regulation of (Ca2+ + Mg2+)-adenosine triphosphatase activity in kidney membranes from streptozocin non-insulin-dependent diabetic rats. 817 49

In NIDDM, first-phase insulin release to glucose is (almost) absent. However, in contrast to older studies which suggested that in NIDDM the B-cell is "blind" for glucose, recent evidence indicates that the B-cell is not insensitive for glucose as far as second phase release is concerned. This suggests that the metabolism of glucose is probably not deranged in NIDDM, since glucose leads to insulin release after it has been metabolized. Hyperglycaemia itself has a deleterious effect on insulin release, so-called glucose toxicity. Various mechanisms have been proposed, whereby hyperglycaemia may diminish insulin release: inhibition of Ca2+ mobilization from the endoplasmic reticulum by glucose-6-phosphate, Ca2+ uptake in the ER by glucose and inhibitory effects of protein kinase C. Whatever may prove to be the underlying mechanism(s), glucose toxicity is unlikely to be the only cause of insulin secretory disturbances in NIDDM, since the glucose level would have to be elevated before it could be toxic. Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by both defects in insulin action and insulin secretion. With regard to the defects in insulin release, much research has originated from two (partly) opposing hypotheses, namely the presence of pancreatic B-cell glucose blindness and the hypothesis of pancreatic B-cell glucose toxicity in NIDDM.
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PMID:Defects in insulin secretion in NIDDM: B-cell glucose insensitivity or glucose toxicity? 844 21

Widely held theories of the pathogenesis of obesity-associated NIDDM have implicated apparently incompatible events as seminal: 1) insulin resistance in muscle, 2) abnormal secretion of insulin, and 3) increases in intra-abdominal fat. Altered circulating or tissue lipids are characteristic features of obesity and NIDDM. The etiology of these defects is not known. In this perspective, we propose that the same metabolic events, elevated malonyl-CoA and long-chain acyl-CoA (LC-CoA), in various tissues mediate, in part, the pleiotropic alterations characteristic of obesity and NIDDM. We review the evidence in support of the emerging concept that malonyl-CoA and LC-CoA act as metabolic coupling factors in beta-cell signal transduction, linking fuel metabolism to insulin secretion. We suggest that acetyl-CoA carboxylase, which synthesizes malonyl-CoA, a "signal of plenty," and carnitine palmitoyl transferase 1, which is regulated by it, may perform as fuel sensors in the beta-cell, integrating the concentrations of all circulating fuel stimuli in the beta-cell as well as in muscle, liver, and adipose tissue. The target effectors of LC-CoA may include protein kinase C sub-types, complex lipid formation, genes encoding metabolic enzymes or transduction factors, and protein acylation. We support the concept that only under conditions in which both glucose and lipids are plentiful will the metabolic abnormality, which may be termed glucolipoxia, become apparent. If our hypothesis is correct that common signaling abnormalities in the metabolism of malonyl-CoA and LC-CoA contribute to altered insulin release and sensitivity, it offers a novel explanation for the presence of variable combinations of these defects in individuals with differing genetic backgrounds and for the fact that it has been difficult to determine whether one or the other is the primary event.
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PMID:Are the beta-cell signaling molecules malonyl-CoA and cystolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? 859 30

Intracellular calcium ([Ca2+]i) and phorbol ester binding were studied in intact platelets of young patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. Our objective was to evaluate disturbances in calcium regulation and signal transduction in platelets of diabetics. [Ca2+]i in platelets of the IDDM group (135 +/- 20 nmol/L) under basal conditions was significantly higher than that of the control group (81 +/- 8 nmol/L, P = .019), whereas at 60 seconds after stimulation with 0.1 National Institutes of Health (NIH) U/mL thrombin, [Ca2+]i in the NIDDM group (484 +/- 36 nmol/L) was significantly higher than that of the controls (347 +/- 22 nmol/L, P = .003) and IDDM group (360 +/- 45 nmol/L, P = .04), respectively. Phorbol 12,13-dibutyrate (PdBu) maximal binding capacity (Bmax) in the IDDM group was significantly lower than that in the control group either under basal conditions or after stimulation with thrombin (P = .0034 and P = .015, respectively). Bmax in the NIDDM group was significantly lower than that in the controls only after stimulation with thrombin (P = .047). The Kd for PdBu of the IDDM group was lower than that of the control group under basal conditions (P = .017). When analyzing the pooled data of all subjects, a significant correlation was observed between Bmax and Kd (under basal conditions, r = .544, P < .0001; after stimulation, r = .601, P < .0001). Our results support the idea that the increased affinity for PdBu may compensate for the decreased binding capacity. We interpret the data as indicating that the change in the binding of phorbol ester to protein kinase C (PKC) units may result in an altered PKC/calcium interaction in the pathogenesis of diabetes mellitus. Our study indicates that such metabolic derangements of [Ca2+]i have already been developing in young diabetic patients.
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PMID:Increased intracellular calcium and altered phorbol dibutyrate binding to intact platelets in young subjects with insulin-dependent and non-insulin-dependent diabetes mellitus. 925 80

We have used differential display to identify genes whose expression is altered in type 2 diabetes thus contributing to its pathogenesis. One mRNA is overexpressed in fibroblasts from type 2 diabetics compared with non-diabetic individuals, as well as in skeletal muscle and adipose tissues, two major sites of insulin resistance in type 2 diabetes. The levels of the protein encoded by this mRNA are also elevated in type 2 diabetic tissues; thus, we named it PED for phosphoprotein enriched in diabetes. PED cloning shows that it encodes a 15 kDa phosphoprotein identical to the protein kinase C (PKC) substrate PEA-15. The PED gene maps on human chromosome 1q21-22. Transfection of PED/PEA-15 in differentiating L6 skeletal muscle cells increases the content of Glut1 transporters on the plasma membrane and inhibits insulin-stimulated glucose transport and cell-surface recruitment of Glut4, the major insulin-sensitive glucose transporter. These effects of PED overexpression are reversed by blocking PKC activity. Overexpression of the PED/PEA-15 gene may contribute to insulin resistance in glucose uptake in type 2 diabetes.
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PMID:PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. 967 3

The incidence of diabetes mellitus has been increased year by year and now 5-6 millions are diabetic patients in Japan. Studies of DCCT and UKPDS concluded that tight control of diabetes was benefit for prevention of diabetic complications in type 1 and type 2 diabetes, respectively. New type of sulfonylurea (glimepiride) has been developed by Hoechst Marion Roussel company which continues clinical trials in Japan. Grimepiride is an insulin sparing sulfonylurea drug for the treatment of type 2 diabetes patients whose high blood glucose cannot be controlled by diet and exercise alone. In Europe and United State glimepiride has been used as a monotherapy or in combination with insulin. Glucose control was effectively observed in type 2 diabetics including obese and hypertensive patients by the drug. Mechanism of sulfonylurea which stimulates insulin release is supposed by binding to a regulatory subunit of plasma membrane ATP-sensitive K+ (KATP) channel. The consequent closure of KATP channel leads to depolarization, opening of voltage-dependent Ca2+ channels, Ca2+ influx, and a rise in intracellular [Ca2+], resulting in insulin secretion. However, it has been suggested that sulfonylurea may have an additional action on secretion, independent of changes in intracellular [Ca2+] but dependent on the activity of protein kinase C (PKC). It is controversial whether or not sulfonylurea is a risky drug to the process of diabetic macroangiopathy, by suppressing KATP channels in the heart.
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PMID:[Sulfonylurea drug--a new sulfonylurea drug for type 2 diabetes]. 1019 56

Animal species with genetic or nutritionally induced insulin resistance, diabetes and obesity (diabesity) may be divided into two broad groups: those with resilient pancreatic beta-cells, e.g. ob/ob mice and fa/fa rats, capable of long-lasting compensatory insulin over-secretion, and those with labile beta-cells in which the secretion pressure leads to irreversible beta-cell degranulation, e.g. db/db mice, Macaca mulatta primates, ZDF diabetic rats. Prominent in this group is the Israeli desert gerbil Psammomys obesus (sand rat), which features low insulin receptor density in liver and muscle. On a diet of relatively high energy, the capacity of insulin to activate the receptor tyrosine kinase (TK) is reduced, in the face of hyperinsulinemia. With the following hyperglycemia, the rising insulin resistance imposes a vicious cycle of insulinemia and glycemia, accentuating the TK activation failure and the beta-cell failure. Among various factors affecting the insulin signaling pathway, multisite phosphorylation, including serine and threonine on the receptor beta-subunit, due to overexpression of certain protein kinase C isoforms, seems to be responsible for the inhibition of the critical step of TK phosphorylation activity. The compromised TK activation is reversible by diet restriction which restores to normal the glycemia and insulinemia. The beta-cell response to long-lasting stimulation and the receptor malfunction in diabesity have implications for a similar etiology in human insulin resistance syndrome and type 2 diabetes, particularly in populations emerging from a food scarce environment into nutritional affluence, inappropriate to the human metabolic capacity. It is suggested that the "thrifty gene" is characterized by a low threshold for insulin secretion and low capacity for insulin clearance. Thus, nutritionally-induced hyperinsulinemia is potentiated and becomes the primary phenotypic expression of the thrifty gene, linked to the insulin receptor signaling pathway malfunction.
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PMID:Cellular mechanism of nutritionally induced insulin resistance: the desert rodent Psammomys obesus and other animals in which insulin resistance leads to detrimental outcome. 1021 43

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