Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucagon-like peptide-I(7-37) [GLP-I(7-37)] is an intestinal peptide with potent insulinotropic activities on pancreatic beta-cells in vivo and in vitro. In earlier studies elevated concentrations GLP-I(7-37) inhibited insulin release and cAMP generation in beta-cells. We now show that the GLP-I(7-37) receptor in the glucose-responsive B-cell line HIT-T15 undergoes rapid and reversible homologous desensitization in response to supraphysiological concentrations of GLP-I(7-37). GLP-I(7-37) stimulated insulin release and cAMP generation in a glucose-dependent biphasic manner with a maximum stimulation at 10 nmol/liter. The first-phase insulin secretory response was reduced by 41% at doses of GLP-I(7-37) of 100 nmol/liter and higher. Preperifusion of B-cells with 100 nmol/liter GLP-I(7-37) for 5 or 10 min reduced a subsequent insulin secretory response to 10 nmol/liter GLP-I(7-37) after hormone washout and recovery periods of 10 min (52% and 55% reduction) or 30 min (33% reduction or full recovery). Preperifusion of HIT-T15 cells with 100 nmol/liter glucagon (10 min) or 100 nmol/liter gastric inhibitory peptide (GIP) (10 min) had no effect on the insulin secretory response to 10 nmol/liter GLP-(7-37). Prior exposure of cells to 100 nmol/liter GLP-(7-37) (10 min) did not alter the GIP-induced (10 nmol/liter) insulin release, but 100 nmol/liter GIP (10 min) reduced the insulin secretion during stimulation with 10 nmol/liter GIP by 56%. These data indicate that: 1) the GLP-I(7-37) receptor is subject to rapid and reversible homologous desensitization and, 2) the GLP-I(7-37) receptor on beta-cells is distinct from that of GIP. The recent finding of elevated GLP-I(7-36)amide levels in subjects with noninsulin-dependent diabetes suggest the possibility that a homologous desensitization of the GLP-I(7-37) receptor might contribute to the impaired insulin secretion in this disorder.
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PMID:Homologous desensitization of the insulinotropic glucagon-like peptide-I (7-37) receptor on insulinoma (HIT-T15) cells. 164 53

NOD/Lt mice harboring a hybrid rat insulin-promoter/SV40 large T-antigen gene spontaneously develop beta-cell adenomas. NIT-1 is a pancreatic beta-cell line established from one of these transgenic mice. Immunocytochemical staining of passage 18 cells showed most contained insulin, with less than 5% containing glucagon, and none containing pancreatic polypeptide or somatostatin. Glucagon content radioimmunoassayed in cell extracts was only 0.27% of the insulin content. Two-hour insulin secretion at 16.5 mM glucose was 638 ng/10(6) cells (41% of intracellular content) compared to only 1.3 ng glucagon (32% of intracellular content). Stimulated insulin secretion was consistently observed in response to 11 and 16.5 mM glucose between passages 11 and 19. At passage 19, both theophylline and tolbutamide stimulated insulin secretion at 5.5 mM glucose. Northern-blot analysis confirmed high levels of insulin mRNA but only trace glucagon mRNA and undetectable somatostatin mRNA. Interferon-gamma (IFN-gamma)-induced MHC class I RNA expression was correlated with markedly increased antigen expression at the cell surface. Similarly, a MHC-linked "occult" class I-like antigen detected by Cr release assay only after exposure of standard NOD/Lt islet cells to IFN-gamma was strongly induced by IFN-gamma in NIT-1 cells. Cell surface MHC class II antigen was not constitutively expressed on NIT-1 cells and could not be detected after IFN-gamma incubation, despite demonstration of IFN-gamma-induced Aa, Ab, and Li invariant-chain RNA transcripts. Similarly IFN-gamma induction of intercellular adhesion molecule 1 (Icam-1) transcripts was not accompanied by demonstrable cell surface expression of ICAM-1 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Jul
PMID:NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse. 164 94

Cultured rat hepatocytes were preincubated with glucagon or a cyclic AMP analogue for up to 24 h and lipid synthesis and secretion were determined during the next 2 h. Glucagon or cyclic AMP did not change the incorporation of choline or glycerol into phosphatidylcholine, or choline into sphingomyelin, in the cells after 0-12 h of preincubation. After 12 h these incorporations were increased. Incorporations into hepatic lysophosphatidylcholine were decreased after preincubation with glucagon or cyclic AMP for 0-12 h, but by 24 h they increased. There was no change in the lysophosphatidylcholine in the medium after preincubation with glucagon or cyclic AMP for up to 6 h, but increases occurred after preincubation from 12 to 24 h. The secretion of triacylglycerol was decreased after preincubation for 0-1 h, but it returned to control values after 4 h. After preincubation for 18-24 h the incorporation of glycerol into secreted triacylglycerol was increased. The results are discussed in relation to the control of lipid metabolism in starvation and diabetes.
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PMID:Biphasic effects of glucagon and cyclic AMP on the synthesis and secretion of lipids by rat hepatocytes. 165 86

The dynamic study of somatostatin secretion was performed in patients with insulin-dependent diabetes mellitus and age- and sex matched volunteers. The basal levels of immunoreactive somatostatin, as well as its response to i.v. Glucagon (1 mg) at 10 and 20 min with consequent hyperglycemia were increased in most of diabetic patients as compared with the healthy controls. Our results suggest that the glucagon test could be used for estimating the somatostatin secretion in diabetes mellitus. This would reveal some impaired interactions between the endocrine function of the pancreas in diabetes mellitus.
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PMID:Increased somatostatin response to glucagon in insulin-dependent diabetes mellitus. 168 18

This study used 10-nm gold particles with 5-7 insulin molecules attached (Au10-Ins) to investigate the site of interaction of insulin with the nuclear envelope during insulin uptake into intact isolated nuclei. Despite its size, and in the absence of ATP, Au10-Ins entered nuclei through the nuclear pore and associated with the heterochromatin. Because Au10-Ins is essentially gold-bovine serum albumin (Au-BSA) with a few insulin molecules attached, the effect of insulin and other growth factors on the nuclear accumulation of BSA coupled to 10-, 15-, and 24-nm-diam colloidal gold particles (Au10-BSA, Au15-BSA, and Au24-BSA) was determined. The Au-BSA complexes were excluded from nuclei in the absence of insulin. Insulin (0.5-100 ng/ml) caused a dose-dependent accumulation of Au10-BSA in the nucleus. The nuclear membrane was shown to be intact by several criteria, therefore, accumulation of Au-BSA occurred via the nuclear pore and was not due to leakage across or through the membrane. Uptake of 15- and 24-nm Au-BSA molecules was not affected by insulin, suggesting the hormone had a limited effect in increasing the functional diameter of the nuclear pores. Glucagon, epidermal growth factor, platelet-derived growth factor, insulinlike growth factor I, and insulin A or B chains did not stimulate the accumulation of Au10-BSA. The insulin-stimulated accumulation of Au10-BSA was blocked by concanavalin A, mimicked by wheat-germ agglutinin, and did not require ATP. The Au10-BSA in the nucleus was associated with heterochromatin, suggesting it bound to a nuclear element.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Feb
PMID:Insulin stimulates accumulation and efflux of macromolecules in isolated nuclei from H35 hepatoma cells. 173 9

The effects of left cervical vagus nerve stimulation on glucagon secretion were studied in streptozotocin-diabetic and age-matched control adult male rats. At two-week intervals, after the induction of streptozotocin-diabetes, streptozotocin-diabetic and age-matched control rats were anesthetized with chloral hydrate (350 mg/kg, ip). Left cervical vagus nerves were electrically stimulated via a Grass stimulator with 5-volt monophasic pulses of 3 msec duration at a frequency of 20 Hz for 1, 2, and 4 min. Arginine-induced glucagon secretion was also determined. Vagus nerve-stimulated (2 and 4 min) glucagon secretion deteriorated as the duration of streptozotocin-diabetes increased. Glucagon secretion in response to vagus nerve stimulation was virtually absent by 12 weeks of streptozotocin-diabetes. However, arginine-induced glucagon secretion was unaffected. Subsequent experiments showed that the defect in glucagon secretion from vagal stimulation occurred concurrently with that seen from insulin-induced hypoglycemia. These results indicate that the impaired hypoglycemia-induced glucagon secretion in long-term streptozotocin-diabetic rats may be correlated with the deterioration of the parasympathetic nervous system transmission in streptozotocin-diabetes.
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PMID:Progressive and concurrent deterioration of vagus-stimulated and hypoglycemia-induced glucagon secretion in streptozotocin-diabetic rats. 173 51

We have investigated the effects of Pro-Met-Asp-Phe-NH2 (PMAP) on insulin and glucagon release from human fetal pancreatic microfragments in vitro. Four batches of precultured microfragments were incubated for 24 hrs in medium containing 5.5 mM glucose, 17 mM glucose, 1 microM PMAP or 1 microM PMAP plus 17 mM glucose. PMAP significantly enhanced both basal and glucose-stimulated insulin release (2.2- and 4.1-fold, respectively). Glucagon secretion was markedly inhibited by glucose (17 mM). PMAP neither affected the basal glucagon release nor potentiated the inhibitory action of glucose on glucagon release. Hence, PMAR selectively regulates insulin production in human fetal islet tissue without affecting glucagon production. Our results suggest that the substances similar or related to PMAP may prove to be of clinical value in drug correction of diabetes mellitus.
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PMID:[Effects of synthetic cholecystokinin analog on hormone secretion in fetal human pancreatic tissue culture]. 177 24

Hormonal changes and whole blood free amino acid levels and their relation to renal function were measured in 12 insulin-dependent diabetic patients after two 10-day periods with a diet consisting of 10% and 20% respectively of the energy as protein. The patients were 15-21 years old and mean duration of diabetes was 12 (5-20) years. Glomerular filtration rate, renal plasma flow, and albumin excretion rate were measured together with plasma concentrations of glucagon, growth hormone, insulin-like growth factor 1 (IGF-1), somatostatin, serum insulin and free amino acids in blood. Glomerular filtration rate was 123 +/- 3 ml/min/1.73 m2 on high protein diet and 113 +/- 3 ml/min/1.73 m2 on low protein diet (p = 0.02). Renal plasma flow was unchanged. Glucagon, IGF-1, branch chained amino acids (BCAA), tyrosine, phenylalanine, lysine, and methionine were increased after the high protein diet. Growth hormone, somatostatin, insulin, and other amino acids remained unchanged. The increase in glomerular filtration rate was significantly correlated to the increase in glucagon, isoleucine, and valine (glucagon r = 0.71, p = 0.01, isoleucine r = 0.59, p = 0.04, valine r = 0.62, p = 0.03). In a multiple regression model the increase in glomerular filtration correlated most strongly to the increase in isoleucine, followed by valine and glucagon. Together these variables explained 88% of the total variance of the change in glomerular filtration rate (r2 = 0.88, p = 0.001). Albumin excretion rate was correlated to IGF-1 (r = 0.86, p less than 0.001) on the high protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1991 Mar
PMID:Indications that branched chain amino acids, in addition to glucagon, affect the glomerular filtration rate after a high protein diet in insulin-dependent diabetes. 180 76

In alloxan-diabetic (A-D) dogs, plasma glucagon does not increase when glycemia is decreased by insulin. Therefore, as in insulin-dependent diabetes mellitus (IDDM), increased glucose utilization is not matched by an increase in hepatic production. To explore further the abnormal effects of insulin on regulation of pancreatic glucagon, we studied content and morphology of pancreatic hormones in six normal (N) dogs, five hyperglycemic A-D (HD) dogs, and in four A-D dogs where normoglycemia was maintained by insulin (ND). Morphometric measurement of islets and of immunocytochemically localized A cells (glucagon) were performed by an image analysis system. In normal pancreas, islets of tail and body were bigger in size (tail = 4850 +/- 376 microns 2, body = 3256 +/- 198 microns 2), than the head (2009 +/- 207 microns 2). Glucagon content was 331 +/- 50 micrograms with a mean concentration of 8.5 +/- 0.9 micrograms/g in N dogs, and did not change in HD dogs (422 +/- 34 micrograms, 9.3 +/- 0.4 micrograms/g). With normoglycemia, glucagon content decreased by 5-fold (p less than 0.001). Morphometry indicated that, although A cell area per islet increased (2.7-fold), islet number decreased (70%), explaining the unchanged glucagon content in HD dogs. This decrease in islet number can also justify the dramatic glucagon decrease in ND dogs. Despite the 70% decrease in islet numbers in HD dogs, pancreatic somatostatin increased 3-fold (9.93 +/- 3.3 to 30.6 +/- 7.2 micrograms), indicating that its islet content was augmented 10-fold. Somatostatin content returned to normal with normoglycemia. Pancreatic insulin content in HD dogs was negligible (55 +/- 23 micrograms) when compared with that in N dogs (5500 micrograms) and it did not increase with normoglycemia. The distinct but markedly diminished insulin and proinsulin peaks in HD dogs nearly disappeared in ND dogs. Thus, in alloxan-diabetic HD dogs, 70% of islets are destroyed. A marked increase in glucagon in residual islets can explain the unchanged islet size despite the absence of B cells; however, the percent increase of somatostatin is larger than that of glucagon. Normoglycemia 1) normalizes somatostatin content, 2) further diminishes insulin and proinsulin synthesis presumably due to lack of hyperglycemic stimulus, and 3) paradoxically decreases pancreatic glucagon content 5-fold below its normal level. We hypothesize that with normalization of plasma insulin, glucagon content in each islet normalizes, but because of destruction of most islets, pancreatic glucagon content becomes extremely low.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Paradoxical reduction in pancreatic glucagon with normalization of somatostatin and decrease in insulin in normoglycemic alloxan-diabetic dogs: a putative mechanism of glucagon irresponsiveness to hypoglycemia. 196 77

To define the spontaneous diurnal variations in glucose regulation during fasting in noninsulin-dependent diabetes (NIDDM), we measured circulating levels of glucose, insulin, C-peptide, GH, cortisol, and glucagon at 15-min intervals in 11 patients with untreated diabetes and 7 matched control subjects studied during a 24-h period. The rates of insulin secretion were derived from the concentrations of C-peptide by deconvolution using a two-compartment mathematical model for C-peptide distribution and metabolism. In both groups of subjects, despite continued fasting, glucose levels stopped declining in the evening and subsequently rose throughout the night to reach a morning maximum. Elevated levels persisted until noon. The morning glucose maximum corresponded to a relative increase of 23.8 +/- 5.5% above the evening nadir in NIDDM patients and 13.2 +/- 4.6% in nondiabetic subjects (P less than 0.05). In NIDDM patients, insulin levels and insulin secretion rates did not parallel the nocturnal glucose changes. In contrast, in control subjects, this nocturnal glucose rise coincided with a similar increase in insulin secretion rates. Cortisol concentrations in patients with NIDDM were higher than those in control subjects throughout the study period (P less than 0.001) and rose earlier in the evening than in control subjects, thus failing to demonstrate the normal nocturnal suppression. In both groups of subjects, the nighttime glucose elevation was temporally and quantitatively correlated with the circadian cortisol rise. GH secretion was increased in the evening and nighttime periods compared to the daytime values, and in NIDDM patients, but not in control subjects, the size of the morning glucose elevation was directly related to the magnitude of this increase in GH secretion (r = 0.88; P less than 0.01). Glucagon concentrations were similar in both groups of subjects and remained essentially constant throughout the study period. We hypothesize that the nocturnal glucose rise that occurs during fasting represents a normal diurnal variation in the set-point of glucose regulation amplified by counterregulatory mechanisms activated by the fasting condition.
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PMID:Nocturnal elevation of glucose levels during fasting in noninsulin-dependent diabetes. 199 13


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