Biomedical subjects

R N Kulkarni

Publications and source records attributed to R N Kulkarni.

At least 19 recordsLinked to original sources

PubMed2005

Microsurgical anatomy of the middle cerebral artery.

BACKGROUND: The microsurgical anatomy of the middle cerebral artery (MCA) is of particular interest to the cerebrovascular surgeon. The purpose of this study was to define the microsurgical anatomy of the MCA and its various branches in the Indian population. METHODS: Ten MCAs were studied from five cadaveric brain specimens. The authors studied the outer diameter, length, branches, perforators and site of these on the main trunk (M1), the division of the main trunk, the secondary trunks and their various cortical branches using the operating microscope under 5-20x magnification. RESULTS: The outer diameter of the MCA main trunk ranges from 2.5 to 4 mm with a mean of 3.35 mm. The superolateral branches consisted of polar temporal artery and anterior temporal artery that had a common origin and sometimes the uncal artery or the accessory uncal artery. Perforators or lenticulostriate arteries were seen in the inferomedial surface all along the length of M1. Eight bifurcations and two trifurcations were noted. Cortical branches and their origin are discussed. CONCLUSION: Although the microsurgical anatomy of the MCA in Indian population correlated with the findings in the western literature, some structural and statistical variations were noted.

Humans↗

PubMed2004

Allelic differences at two loci govern different mechanisms of intraflower self-pollination in self-pollinating strains of periwinkle.

Periwinkle [Catharanthus roseus (L.) G. Don], an ornamental and medicinal plant, is a self-compatible, insect-pollinated plant species in which intraflower self-pollination does not occur because of spatial separation of the stigma and anthers. Recently three self-pollinating strains-MJ, VI, and OR-were identified. Self-pollination in these strains was found to be brought about by continuous increase in gynoecium length from anthesis to self-pollination, in contrast to non-self-pollinating strains, in which the stigma remained below the base of the anthers from anthesis to flower drop. Self-pollination in these strains was found to be controlled by duplicate, recessive genes. Self-pollination in strains MJ and VI was brought about by an increase in gynoecium length resulting from an increase in the length of the ovary, while in the strain OR, the increase in gynoecium length was because of an increase in the length of the style from anthesis to self-pollination. The three strains were intercrossed to determine the relationship between genes governing self-pollination in these strains. The F(1) plants and all plants of the F(2) generation of the cross MJ x VI exhibited self-pollination that was brought about by an increase in the length of the ovary, indicating that the same genes were involved in these two strains. The F(1) plants of crosses OR x MJ and OR x VI, exhibited self-pollination that was brought about by an increase in the length of the ovary, indicating that self-pollination brought about by an increase in the length of the ovary was dominant over self-pollination brought about by an increase in the length of the style. In the F(2) and backcross [(OR x MJ) x OR and (OR x VI) x OR] generations, both self-pollinating and non-self-pollinating plants were observed. The ratio of plants with self-pollination brought about by an increase in the length of the ovary, non-self-pollinating plants, and plants with self-pollination brought about by an increase in the length of the style in the F(2) and backcross generations fit 9:6:1 and 1:2:1 ratios, respectively. All plants of the backcrosses [(OR x MJ) x MJ and (OR x VI) x VI] exhibited self-pollination brought about by an increase in the length of the ovary. The results thus supported the earlier finding that self-pollination in the studied strains was controlled by duplicate, recessive genes and suggested that three alleles at two loci determine the occurrence or nonoccurrence of intraflower self-pollination in periwinkle.

Alleles↗

PubMed2002

beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass.

Regulation of glucose homeostasis by insulin depends on the maintenance of normal beta-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells. Igf1 has been shown to influence beta-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r(+/-)) are bred with mice lacking insulin receptor substrate 2 (Irs2(-/-)), the resulting compound knockout mice show a reduction in mass of beta-cells similar to that observed in pancreas of Igf1r(-/-) mice (ref. 11), suggesting a role for Igf1r in growth of beta-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a beta-cell-specific knockout of Igf1r (betaIgf1r(-/-)). These mice show normal growth and development of beta-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in beta-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet beta-cell development, but participates in control of differentiated function.

Animals↗

PubMed2002

Role of socio-economic factors and cytology in cervical erosion in reproductive age group women.

A cross-sectional study involving 357 females in the reproductive age group (15-44) was conducted in an urban community of Nagpur with the objective of studying the role of socio-economic factors & cytology in cervical erosion. Cervical erosion was detected in 82 (22.96%) females. Out of these mild dysplasia was seen in 9.75% females & moderate dysplasia in 2.43% females. High percentages of inflammatory smears i.e. (75.68%) were obtained in women with cervical erosion. Cervical erosion was more common in illiterate & women with low literacy status as compared to women with higher education. Majority of cases of cervical erosion (75.6%) were detected in women with high parity. A statistically significant association was found between lower socio-economic status, early age at marriage & ocurrence of cervical erosion (p<0.001 & p<0.01 respectively). The study concludes that socio-economic factors such as illiteracy and low literacy status, lower socio-economic status, early age at marriage and high parity are contributory for the occurrence of cervical erosion and regular cytological screening by Pap smear will help in early detection of carcinoma cervix and thereby reduce the morbidity and mortality caused by the same.

Adult↗

PubMed2001

Evidence for a circulating islet cell growth factor in insulin-resistant states.

Insulin resistance is a feature of many common disorders including obesity and type 2 diabetes mellitus. In these disorders, the beta-cells compensate for the insulin resistance for long periods of time with an increase in secretory capacity, an increase in beta-cell mass, or both. To determine whether the beta-cell response might relate to a circulating growth factor, we have transplanted normal islets under the kidney capsule of normoglycemic insulin-resistant mice with two different models of insulin resistance: lean mice that have a double heterozygous deletion of the insulin receptor and insulin receptor substrate-1 (DH) or the obese, hyperglycemic ob/ob mice. In the grafts transplanted into both hosts, there was a marked increase in beta-cell mitotic activity and islet mass that was comparable with that observed in the endogenous pancreas. By contrast, islets of the DH mouse transplanted into normal mice showed reduced mitotic index. These data suggest the insulin resistance is associated with a circulating islet cell growth factor that is independent of glucose and obesity.

Animals↗

PubMed2001

Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells.

Insulin signaling is mediated by a complex network of diverging and converging pathways, with alternative proteins and isoforms at almost every step in the process. We show here that insulin activates the transcription of its own gene and that of the beta cell glucokinase gene (betaGK) by different mechanisms. Whereas insulin gene transcription is promoted by signaling through insulin receptor A type (Ex11-), PI3K class Ia, and p70s6k, insulin stimulates the betaGK gene by signaling via insulin receptor B type (Ex11+), PI3K class II-like activity, and PKB (c-Akt). Our data provide evidence for selectivity in insulin action via the two isoforms of the insulin receptor, the molecular basis being preferential signaling through different PI3K and protein kinases.

Calcium Channel Blockers↗

PubMed2000

Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in beta -cells.

The signaling pathway by which insulin stimulates insulin secretion and increases in intracellular free Ca(2+) concentration ([Ca(2+)](i)) in isolated mouse pancreatic beta-cells and clonal beta-cells was investigated. Application of insulin to single beta-cells resulted in increases in [Ca(2+)](i) that were of lower magnitude, slower onset, and longer lifetime than that observed with stimulation with tolbutamide. Furthermore, the increases in [Ca(2+)](i) originated from interior regions of the cell rather than from the plasma membrane as with depolarizing stimuli. The insulin-induced [Ca(2+)](i) changes and insulin secretion at single beta-cells were abolished by treatment with 100 nm wortmannin or 1 micrometer thapsigargin; however, they were unaffected by 10 micrometer U73122, 20 micrometer nifedipine, or removal of Ca(2+) from the medium. Insulin-stimulated insulin secretion was also abolished by treatment with 2 micrometer bisindolylmaleimide I, but [Ca(2+)](i) changes were unaffected. In an insulin receptor substrate-1 gene disrupted beta-cell tumor line, insulin did not evoke either [Ca(2+)](i) changes or insulin secretion. The data suggest that autocrine-activated increases in [Ca(2+)](i) are due to release of intracellular Ca(2+) stores, especially the endoplasmic reticulum, mediated by insulin receptor substrate-1 and phosphatidylinositol 3-kinase. Autocrine activation of insulin secretion is mediated by the increase in [Ca(2+)](i) and activation of protein kinase C.

Animals↗

PubMed2000

Knockout mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes mellitus.

The failure of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production represents two of the fundamental pathophysiologic lesions in type 2 diabetes mellitus (DM). Defining insulin action at the molecular level, therefore, provides the critical background against which to elucidate the mechanisms of insulin resistance that underlie type 2 DM, obesity and many other disorders. Over the past two decades substantial progress has been made in identifying many of the molecular mechanisms involved in insulin signaling. Much of this progress has been due to the use of homologous recombinant gene targeting. The present review examines the various insights that have been provided by studies of knockout mice strains. Taken together, the results present the possibility of a unifying hypothesis for type 2 DM, in which insulin resistance in the beta-cell synergizes with insulin resistance in the periphery to produce the two classic defects of this disease: relative hypoinsulinemia and peripheral insulin resistance.

Animals↗

PubMed2000

Glibenclamide but not other sulphonylureas stimulates release of neuropeptide Y from perifused rat islets and hamster insulinoma cells.

We have studied the effects of first and second generation sulphonylureas on the release of insulin and neuropeptide tyrosine (NPY) from hamster insulinoma tumour (HIT T15) cells and isolated rat islets. In the presence of 5.5 mmol/l glucose all sulphonylureas stimulated insulin release from the HIT cells (P<0.01 ANOVA, n> or =4) but only glibenclamide (GLIB, 10 micromol/l) stimulated the release of NPY (mean+/-s.e.m. control 11.1+/-1.3 vs GLIB 28.4+/-4.1 fmol/h per 10(6) cells, P<0001, n=16). In isolated perifused rat islets both glibenclamide (10 micromol/l) (control 3.5+/-0.3 vs GLIB 6. 3+/-0.2 fmol/min per islet, P<0.01, n=6) and tolbutamide (50 micromol/l) (control 4.7+/-0.1 vs TOLB 6.7+/-0.3 fmol/min per islet, P<0.01, n=6) enhanced glucose (8 mmol/l)-stimulated insulin release. However, only glibenclamide stimulated the release of NPY from the islets (control 3.4+/-0.8 vs GLIB 24.5+/-5 attomol/min per islet, P<0.01, n=6). Similar results were obtained in islets isolated from dexamethasonetreated rats. Glibenclamide treatment of HIT cells showed a prompt insulin release (10 min) while NPY secretion was slower (60 min), suggesting that internalization of the sulphonylurea is required to stimulate NPY release. Glibenclamide, the most common oral therapeutic agent in type 2 diabetes mellitus, is associated with release of the autocrine insulin secretion inhibitor, NPY.

Animals↗

PubMed2000

A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes.

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.

Acute-Phase Reaction↗

PubMed2000

Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.

The liver plays a central role in the control of glucose homeostasis and is subject to complex regulation by substrates, insulin, and other hormones. To investigate the effect of the loss of direct insulin action in liver, we have used the Cre-loxP system to inactivate the insulin receptor gene in hepatocytes. Liver-specific insulin receptor knockout (LIRKO) mice exhibit dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations are paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the LIRKO liver exhibits morphological and functional changes, and the metabolic phenotype becomes less severe. Thus, insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function.

Aging↗

PubMed1999

Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes.

Dysfunction of the pancreatic beta cell is an important defect in the pathogenesis of type 2 diabetes, although its exact relationship to the insulin resistance is unclear. To determine whether insulin signaling has a functional role in the beta cell we have used the Cre-loxP system to specifically inactivate the insulin receptor gene in the beta cells. The resultant mice exhibit a selective loss of insulin secretion in response to glucose and a progressive impairment of glucose tolerance. These data indicate an important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell and suggest that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type 2 diabetes.

Alleles↗

PubMed1999

Influence of plant growth stage on the essential oil content and composition in Davana (Artemisia pallens wall.).

The influence of three plant growth stages (full emergence of flower heads, anthesis, and initiation of seed set) on the essential oil content and composition in Davana (Artemisia pallens Wall) was investigated over two successive seasons. The essential oil content was found to be higher at the full emergence of flower heads than at anthesis and initiation of seed set stages. The contents of davanone, the major constituent of davana oil, and linalool decreased while those of (Z)- and (E)-methyl cinnamate, (E)-ethyl cinnamate, bicyclogermacrene, davana ether, 2-hydroxyisodavanone, and farnesol increased from flower heads emergence stage to the initiation of seed set stage. These results support the general practice of harvesting the crop at full bloom stage. Five compounds, viz., (Z)- and (E)-methyl cinnamates, (Z)- and (E)-ethyl cinnamates, and geranyl acetate, were identified for the first time in davana oil.

Artemisia↗

PubMed1999

Altered function of insulin receptor substrate-1-deficient mouse islets and cultured beta-cell lines.

Insulin receptor substrate-1 (IRS-1) is pivotal in mediating the actions of insulin and growth factors in most tissues of the body, but its role in insulin-producing beta islet cells is unclear. Freshly isolated islets from IRS-1 knockout mice and SV40-transformed IRS-1-deficient beta-cell lines exhibit marked insulin secretory defects in response to glucose and arginine. Furthermore, insulin expression is reduced by about 2-fold in the IRS-1-null islets and beta-cell lines, and this defect can be partially restored by transfecting the cells with IRS-1. These data provide evidence for an important role of IRS-1 in islet function and provide a novel functional link between the insulin signaling and insulin secretion pathways. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Animals↗

PubMed1998

Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells.

Neuropeptide Y (NPY) has been shown to inhibit insulin secretion from the islets of Langerhans. We show that insulin secretion in the insulinoma cell line RIN 5AH is inhibited by NPY. 125I-Peptide YY (PYY) saturation and competition-binding studies using NPY fragments and analogues on membranes prepared from this cell line show the presence of a single class of NPY receptor with a Y1 receptor subtype-like profile. Inhibition of insulin secretion in this cell line by NPY fragments and analogues also shows a Y1 receptor-like profile. Both receptor binding and inhibition of insulin secretion showed the same orders of potency with NPY > [Pro34]-NPY > NPY 3-36 >> NPY 13-36. The Y1 receptor antagonist, BIBP 3226, blocks NPY inhibition of insulin secretion from, and inhibits 125I-PYY binding to, RIN 5AH cells. Northern blot analysis using a Y1-receptor specific probe shows that NPY Y1 receptors are expressed by RIN 5AH cells. Y5 receptors are not expressed in this cell line. Neuropeptide Y inhibition of insulin secretion is blocked by incubation with pertussis toxin, implying that the effect is via a G-protein (Gi or Go) coupled receptor. Neuropeptide Y inhibits the activation of adenylyl cyclase by isoprenaline in RIN 5AH cell lysates, and the stimulation of cAMP by glucagon-like peptide-1 (7-36) amide (GLP-1). It also blocks insulin secretion stimulated by GLP-1, but not by dibutyryl cyclic AMP. Hence, we suggest that NPY inhibits insulin secretion from RIN 5AH cells via a Y1 receptor linked through Gi to the inhibition of adenylyl cyclase.

Adenylyl Cyclase Inhibitors↗

PubMed1998

Metabolic responses to repeated infusions of identical doses of norepinephrine in chronically energy deficient human subjects.

The physiological effects of three 30 min infusions of identical doses of norepinephrine (0.15 microgram/kg FFM/min) separated by 60 min intervals were assessed in well nourished (WN; n = 6) and chronically energy deficient (CED; n = 6) subjects. Each subject also underwent control, vehicle infusions with 0.9 per cent saline on a separate day. Oxygen consumption (VO2) was significantly higher during the third infusion of NE as compared to the first in both groups. This increment in VO2 occurred despite similar plasma peak NE levels in both infusions. Increments in plasma glucose and free fatty acids were also similar during the first and third infusions. The study demonstrates that thermogenic potentiation which we had earlier demonstrated in WN subjects, occurs in CED subjects as well. Thermogenic potentiation is not associated with altered plasma NE kinetics or mobilisation of substrates.

Adolescent↗

PubMed1997

Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.

Obesity is associated with diabetes, and leptin is known to be elevated in obesity. To investigate whether leptin has a direct effect on insulin secretion, isolated rat and human islets and cultured insulinoma cells were studied. In all cases, mouse leptin inhibited insulin secretion at concentrations within the plasma range reported in humans. Insulin mRNA expression was also suppressed in the cultured cells and rat islets. The long form of the leptin receptor (OB-Rb) mRNA was present in the islets and insulinoma cell lines. To determine the significance of these findings in vivo, normal fed mice were injected with two doses of leptin. A significant decrease in plasma insulin and associated rise in glucose concentration were observed. Fasted normal and leptin receptor-deficient db/db mice showed no response to leptin. A dose of leptin, which mimicked that found in normal mice, was administered to leptin-deficient, hyperinsulinemic ob/ob mice. This caused a marked lowering of plasma insulin concentration and a doubling of plasma glucose. Thus, leptin has a powerful acute inhibitory effect on insulin secretion. These results suggest that the action of leptin may be one mechanism by which excess adipose tissue could acutely impair carbohydrate metabolism.

Animals↗

PubMed1997

Possible evidence for endogenous production of a novel galanin-like peptide.

Galanin mRNA and peptide are not detectable in normal islets. We studied the effect of galanin antagonists on insulin secretion in the rat beta cell line, RIN5AH, and in perifused rat islets. In RIN cell membranes galanin and its antagonists showed high affinity for 125I-galanin binding sites [Kd: (galanin) 0.03+/-0.01; Ki for galanin antagonists: (C7) 0.12+/- 0.02, (M35) 0.21+/-0.04, and (M40) 0.22+/-0.03 nM, mean+/- SEM, n = 4]. Galanin (1 microM) inhibited glucose-induced insulin release in islets (control 21.2+/-1.5 vs. galanin 4.5+/-0.2 fmol/islet per min, P < 0.001, n = 6) and RIN5AH cells (control 0.26+/-0.01 vs. galanin 0.15+/-0.02 pmol/10(6) cells per h, P < 0.001, n = 9). In RIN5AH cells, all antagonists blocked the inhibitory effects of galanin and stimulated insulin release in the absence of galanin. C7 and M40 (1 microM) alone significantly stimulated glucose-induced insulin secretion. Purified porcine galanin antibody (GAb) enhanced glucose-induced insulin release from islets (control 100+/- 16.3% vs. GAb 806.1+/-10.4%, P < 0.001, n = 6), and RIN5AH cells (control 100+/-9.6% vs. GAb 149+/-6.8%, P < 0. 01, n = 6). Western blotting of dexamethasone-treated islet extracts using GAb showed a specific band of similar molecular weight to porcine galanin not detected using a rat specific galanin antibody. One possible explanation for these results is the presence of an endogenous galanin-like peptide.

Amino Acid Sequence↗