Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT), a tolbutamide modified frequently sampled intravenous glucose tolerance test, and a glucagon test to examine for a possible early beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues.
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PMID:Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation. 907 19

In the present series of 204 patients with NIDDM, 37 were lean and 35 obese. Mean FBG and HbA1C were significantly higher (P<0.02 and <0.01) in the former. Serum lipids such as total cholesterol (Tc) and triglycerides (Tg) were lower (P<0.05) in the lean while HDLc values were similar. Eight lean patients and 6 obese (Mean BMI : 15.7 vs.27.4) having similar age (48.0 vs 47.7 years) and mean duration of diabetes (4.6 vs 4.2 years) were subjected to the study of insulin and C-peptide status as well as beta cell reserve. The mean basal serum insulin (IRI) level was lower in the lean (15.3 vs. 28.9 mu u/ml ; P<0.05) while there was no statistical difference in the basal C-peptide values. Serum samples analysed 2 hours after 75 G of oral glucose and 1 mg I.V. glucagon (Novo) on two consecutive occasions for IRI and C-peptide responses revealed remarkable differences. The rise in IRI was significantly lower (p<0.01) in the lean after oral glucose and glucagon as compared to the obese. But the C-peptide values did not reveal significant difference suggesting similar reserve in beta cell function in both these groups of patients with NIDDM. The disparity between IRI and C-peptide levels observed was most likely due to excess extraction of insulin by the liver in lean-NIDDM, leading to lower peripheral levels. This phenomenon accounts for the occurrence of severe hyperglycemia inspite of good beta cell function in lean NIDDM.
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PMID:Lean (underweight) NIDDM - peculiarities and differences in metabolic and hormonal status - a pilot study. 908 65

In 1981-1982, 5699 persons representing 92.9% of the total population aged 60-74 years living in Fredericia, Denmark, were interviewed about a possible history of diabetes and had a fasting blood glucose measured. A total of 236 gave a positive history of diabetes; 88 had one fasting blood glucose of 7 mmol/L or more. For each of these probands, an age- and gender-matched control person with normal fasting blood glucose and no history of diabetes was selected randomly. Of the 236, 91.5% had NIDDM as judged by glucagon-stimulated C-peptide tests. At the end of December 1995, the participants were traced through the National Register and their status (alive or dead) was determined. The date of death was confirmed. The median observation time from screening and inclusion in the study till death or the end of the observation period in December 1995 was 12.81 years, the maximum was 14.91, and the 25th and 75th percentile values were 6.36 and 13.94 years, respectively. At the end of 1995, 165 (74.4%) of 228 persons with known diabetes at the time of ascertainment had died opposed to 90 (40.4%) of the 223 nondiabetic control persons. The difference is statistically highly significant (p < 0.00001, log-rank test). Within the first 5 years of observation, 42.9% of diabetic men died and only 22.5% of non-diabetic men. This percentage of deaths in diabetic men was found already in the 60-64 year age interval (46.2%). The mortality rate for the non-diabetic population seems to increase later. After 13 years of observation, 74 (81.3%) of 91 men with known diabetes had died, in the age-matched control men, 50 (56.2%) of 89 (p = 0.00006). Ninety-one (66.4%) of 137 diabetic women had died: 40 (29.9%) of 134 control women (p < 0.00001). The difference between mortality in diabetic men and women, and between nondiabetic men and women is highly significant (p = 0.00285 and 0.00001, respectively). The over-mortality of established diabetic persons decreases with age. In the age group 60-74 years, the over-mortality is about 2.5 without gender difference.
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PMID:Over-mortality as related to age and gender in patients with established non-insulin-dependent diabetes mellitus. 910 91

As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affected sib pairs defined as having a fasting plasma glucose value of >6.1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load. No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 years of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further analyses.
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PMID:Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs. 916 80

To clarify the mechanism(s) of the antidiabetic effects of truncated glucagon-like peptide-1 (GLP-1) in diabetics, we examined its insulinotropic and extrapancreatic effects in a newly established strain of spontaneously non-insulin-dependent diabetic (NIDDM) rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, that received a continuous infusion of truncated GLP-1 620 pmol/d/kg (G group, n = 12) or of vehicle (V group, n = 12) for 4 weeks by Alzet pump. Nonfasting plasma glucose levels were significantly lower (P < .05) in the G group than in the V group (7.0 +/- 0.67 v 9.1 +/- 1.7 mmol/L), and fasting plasma immunoreactive insulin (IRI) levels were lower in the former than in the latter (0.63 +/- 0.31 v 0.78 +/- 0.25 nmol/L). At day 15 of infusion, the G group showed an attenuated plasma glucose response to an oral glucose load, but had plasma IRI levels comparable to those in the V group. A long-term infusion of truncated GLP-1 increased the glucose infusion rate (GIR) significantly (P < .05) during a euglycemic-hyperinsulinemic clamp test (59.0 +/- 14.8 mumol/kg/min for group G v 38.9 +/- 12.2 for group V), but hepatic glucose output (HGO) did not differ significantly for either group. Uptake of 2-deoxy-D-glucose (2DG) by peripheral muscles in the G group was as much as 2.4-fold higher than in the V group (5.52 +/- 2.04 v 2.29 +/- 0.97 mumol/100 g muscle weight/min). We conclude from these data that truncated GLP-1, in addition to its well-known incretin effect, is capable of augmenting insulin action in peripheral tissues of diabetics, which can contribute, in part, to improve glucose intolerance in OLETF rats.
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PMID:Extrapancreatic action of truncated glucagon-like peptide-I in Otsuka Long-Evans Tokushima Fatty rats, an animal model for non-insulin-dependent diabetes mellitus. 922 26

We have studied the impact of liquid diets formulated for complete or supplemental enteral nutrition of type II, non insulin-dependent (NIDDM) diabetics on carbohydrate homeostasis. To achieve this, liquid formula tolerance tests were performed in NIDDM patients under an oral treatment regimen with a combination of diet plus glibenclamide (7 men, 3 women, age: 56 +/- 11 years; mean body mass index of 26.2 +/- 3.6 kg/m2). After an overnight fast, each patient received the usual morning medication and, thereafter, ingested formula diet in randomized order with 10 day intervals between tests. 500 ml were administered of either a standard liquid diet (Biosorb Sonde), a fibre containing diet (Biosorb Plus Sonde), or a carbohydrate modified, fructose containing "diabetes" diet (Fresubin Diabetes) (carbohydrate contents of approximately equal to 60 g, respectively). Blood samples were collected over 180 min. Considering minor variations in the nutritional values of the diets, IR-insulin, IR-C-peptide, IR-glucose-dependent insulinotropic polypeptide (GIP), and IR-glucagon-like peptide. 1 (GLP-1) in plasma did not significantly differ between the study groups. After ingestion of Biosorb Sonde area under the curve glucose was greater than that seen after uptake of fibre containing or carbohydrate modified, i.e. fructose containing "liquid diabetes diets". All diets challenged the entero-insular axis in non-insulin dependent diabetics to a comparable extent. This data does not support the contention to employ special "diabetes" formulas for enteral nutrition of patients with NIDDM.
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PMID:No apparent benefit of liquid formula diet in NIDDM. 922 8

Non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. There are various pharmacological approaches to improving glucose homeostasis, but those currently used in clinical practice either do not succeed in restoring normoglycaemia in most patients or fail after a variable period of time. For glycaemic regulation, 4 classes of drugs are currently available: sulphonylureas, biguanides (metformin), alpha-glucosidase inhibitors (acarbose) and insulin, each of which has a different mode and site of action. These standard pharmacological treatments may be used individually for certain types of patients, or may be combined in a stepwise fashion to provide more ideal glycaemic control for most patients. Adjunct treatments comprise a few pharmacological approaches which may help to improve glycaemic control by correcting some abnormalities frequently associated with NIDDM, such as obesity (serotoninergic anorectic agents) and hyperlipidaemia (benfluorex). There is intensive pharmaceutical research to find new drugs able to stimulate insulin secretion (new sulphonylurea or nonsulphonylurea derivatives, glucagon-like peptide-1), improve insulin action (thiazolidinediones, lipid interfering agents, glucagon antagonists, vanadium compounds) or reduce carbohydrate absorption (miglitol, amylin analogues, glucagon-like peptide-1). Further studies should demonstrate the superiority of these new compounds over the standard antidiabetic agents as well as their optimal mode of administration, alone or in combination with currently available drugs.
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PMID:Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Achievements and future developments. 927

We student basal, glucose- and glucagon-induced insulin secretion in non-insulin diabetes mellitus (NIDDM) patients in relation to body mass index (BMI) and fasting serum glucose (FBS) level. A total of 46 NIDDM patients and 22 control subjects with varying degrees of BMI and FBS were given 100 g of oral glucose and 1 mg of intravenous glucagon on separate days. C-peptide response to glucose, but not basal serum C-peptide and C-peptide response to glucagon, was significantly lower in NIDDM than in controls (P < 0.001). FBS was inversely correlated with C-peptide response to glucose in NIDDM patients (r = -0.67, P < 0.001), but not with basal C-peptide level and C-peptide response to glucagon. On the other hand, BMI was positively correlated with basal serum C-peptide level both in NIDDM (r = 0.60, P < 0.001) and in control subjects (r = 0.74, P < 0.001). In 15 poorly controlled NIDDM patients, the tests were repeated after insulin treatment for 10-14 days. C-peptide response to glucose significantly increase, but not to a level in control subjects, after glycemic control. Basal serum C-peptide level and the C-peptide response to glucagon decreased after glycemic control to significantly lower levels than those in the baseline and those in control subjects. These results suggest that beta cell secretory reserve is reduced in moderate to severe NIDDM patients.
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PMID:Differential effects of ambient blood glucose level and degree of obesity on basal serum C-peptide level and the C-peptide response to glucose and glucagon in non-insulin-dependent diabetes mellitus. 930 37

Studies examining small groups of type 2-(NIDDM) diabetic patients have shown the potential of glucagon-like peptide 1 (GLP-1) to normalize fasting hyperglycaemia. Patient characteristics determining the size of the effect have not been reported. Therefore, the results of four studies were analysed. Exogenous GLP-1 was administered i.v. or s.c. in 37 type 2-diabetic patients, age 60 +/- 8 years; BMI 28.2 +/- 5.3 kg/m2; HbA1c 10.6 +/- 1.6%; diabetes duration 10 +/- 6 years, treatment with sulfonylureas, n = 33, metformin, n = 11, acarbose, n = 3. Results were analysed using repeated measures analysis of variance and multiple regression analysis. Exogenous GLP-1 lowered fasting plasma glucose within 4-5 h from 12.8 +/- 2.5 to 5.3 +/- 1.3 mmol/l (placebo: 12.8 +/- 2.3 to 10.0 +/- 2.2; p < 0.0001 for the interaction of treatment and time). Only fasting glycaemia (p = 0.0085) and the route (i.v. vs. s.c.; p = 0.05), but not gender, age, BMI, HbA1c, diabetes duration, treatment with sulfonylureas, metformin or acarbose, were significant predictors of the plasma glucose concentrations reached after the administration of GLP-1 (variation: 3.4-8.5 mmol/l). In conclusion, GLP-1 is able to normalize plasma glucose in all type 2-diabetic patients studied. This analysis underlines the great therapeutic potential of GLP-1.
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PMID:Glucagon-like peptide 1 and its potential in the treatment of non-insulin-dependent diabetes mellitus. 937 Jan 6

NIDDM is associated with excessive rates of endogenous glucose production in both the postabsorptive and postprandial states. To determine whether this is due to an intrinsic increase in hepatic sensitivity to glucagon, 9 NIDDM and 10 nondiabetic subjects were studied on three occasions. On each occasion, glycogen was labeled the evening before the study with subjects ingesting meals containing [6-3H]galactose. Beginning at 6:00 A.M. on the following morning, somatostatin was infused to inhibit endogenous hormone secretion. Insulin concentrations were maintained constant at basal levels (defined as that necessary to keep glucose at approximately 5 mmol/l) in each individual. On one occasion, glucagon was infused at a rate of 0.65 ng x kg(-1) x min(-1) throughout the experiment, resulting in glucagon concentrations of approximately 130 pg/ml and a slow but comparable fall in endogenous glucose production with time in both groups. On the other two occasions, the glucagon infusion was increased at 10:00 A.M. to either 1.5 or 3.0 ng x kg(-1) x min(-1), resulting in an increase in glucagon concentrations to approximately 180 and 310 pg/ml, respectively. The increment in endogenous glucose production (i.e., area above basal) did not differ in diabetic and nondiabetic subjects during either the 1.5 ng x kg(-1) x min(-1) (0.75 +/- 0.055 vs. 0.78 +/- 0.048 mmol/kg) or 3.0 ng x kg(-1) x min(-1) (1.06 +/- 0.066 vs. 1.10 +/- 0.073 mmol/kg) glucagon infusions. In contrast, the amount of [6-3H]glucose released from glycogen was lower (P < 0.05) in the diabetic than nondiabetic subjects during both glucagon infusions. The specific activity of glycogen, calculated as the integrated release of [6-3H]glucose divided by the integrated release of unlabeled glucose, was lower (P < 0.05) in diabetic subjects than in nondiabetic subjects during both the 1.5 ng x kg(-1) x min(-1) (19.0 +/- 3.9 vs. 41.4 +/- 5.7 dpm/micromol) and 3.0 ng x kg(-1) x min(-1) (19.1 +/- 3.1 vs. 36.5 +/- 7.2 dpm/micromol) glucagon infusions, implying that a greater portion of the glucose released from glycogen was derived from the indirect pathway. We concluded that although NIDDM is not associated with an intrinsic alteration in hepatic sensitivity to glucagon, it does alter the relative contributions of the direct and indirect pathways to nocturnal glycogen synthesis.
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PMID:Assessment of hepatic sensitivity to glucagon in NIDDM: use as a tool to estimate the contribution of the indirect pathway to nocturnal glycogen synthesis. 939 88


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