RESUMO
CONTEXT: A patient with diabetes mellitus, who participated in a study with intravenous administration of GLP-1, was later found to have Cushing's disease (markedly elevated 24 h urinary cortisol excretion and inadequate suppression of fasting cortisol with 2 mg dexamethasone). His diabetic state disappeared (2 h plasma glucose after 75 g oral glucose 159 mg/dl=IGT) after successful pituitary surgery (normal 24 h urinary cortisol excretion and adequate cortisol suppression with 2 mg dexamethasone). OBJECTIVE: The present analysis was undertaken to compare GLP-1 actions on fasting glycemia in diabetes mellitus due to Cushing's disease with GLP-1 actions in typical type 2 diabetes. DESIGN AND METHODS: GLP-1 (1.2 pmol/kg/min) and placebo had been infused into ten patients with diabetes mellitus over 4 h in the fasting state. The results from the patient with Cushing's disease (C) were compared to the data from the remaining nine patients with type 2 diabetes (D). RESULTS: Within 4 h glucose decreased from basal (C: 12.9; D: 12.9+/-0.7 mmol/l) to normal fasting values (C: 5.0; D: 4.9+/-0.4 mmol/l). The stimulation of insulin secretion and suppression of glucagon secretion was similar in the patient with Cushing's disease compared to those with type 2 diabetes. CONCLUSIONS: The insulinotropic, glucagonostatic and glucose-lowering actions of GLP-1 in a patient with diabetes mellitus due to cortisol excess were similar to actions in typical type 2 diabetes. Therefore incretin mimetics might be a novel therapeutic strategy for the treatment of glucocorticoid-induced diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Hipersecreção Hipofisária de ACTH/diagnóstico , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etiologia , Feminino , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hidrocortisona/efeitos adversos , Hidrocortisona/sangue , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/sangue , Hipersecreção Hipofisária de ACTH/complicaçõesRESUMO
AIMS: To compare the efficacy and safety of acarbose and metformin when added to sulphonylurea therapy in diabetic patients insufficiently controlled with sulphonylureas alone. METHODS: A 12-week, single-centre, placebo-controlled study, with 89 patients randomized to receive acarbose (100 mg t.d.s.), metformin (850 mg b.d.) or placebo in addition to their sulphonylurea therapy. The study was double-blinded with respect to acarbose/placebo and single-blinded for metformin/ acarbose and metformin/placebo. Patients started a strict dietary regimen 1 week before receiving their first dose of acarbose, metformin or placebo. This regimen was individually adjusted to metabolic status and energy requirements. RESULTS: The primary endpoint, HbA1c, decreased from baseline in all three groups after 12 weeks. The decrease was greater in the two groups receiving active therapy compared with placebo (acarbose -2.3+/-0.32%; metformin -2.5+/-0.16%; placebo -1.3+/-0.34%). There was no significant difference between acarbose and metformin (P=0.65). Differences between both active therapies and placebo were statistically significant (acarbose P < or = 0.01; metformin P < or = 0.004). Reductions in body weight over the treatment period were seen in all three groups and were greatest in the acarbose group (median weight reduction: acarbose 3.5 kg; metformin, 1.0 kg; placebo 1.4 kg). There were no significant differences in the incidence of gastrointestinal side-effects between the three groups and all regimens were generally well tolerated. CONCLUSION: The results of the study demonstrate the equivalence of acarbose and metformin for improving metabolic control in patients insufficiently controlled with diet and sulphonylureas.
Assuntos
Acarbose/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Acarbose/efeitos adversos , Idoso , Glicemia/metabolismo , Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/dietoterapia , Feminino , Alimentos , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Placebos , Triglicerídeos/sangue , Redução de PesoRESUMO
GLP-1 (7-36 amide) normalizes fasting plasma glucose in NIDDM patients. It was the aim to study the effect of overnight intravenous GLP-1 (7-36 amide) on the following 24 h-glucose profiles. Ten NIDDM patients (7 female, 3 male; age 62 +/- 4 y., BMI (Body-Mass-Index) 29.6 +/- 3.9 kg/m2, duration 10 +/- 7 y., HbA1c 10.9 +/- 1.3% (normal 4.0-6.1%), treated with glibenclamide and/or metformin) were studied on two occasions in random order: Either GLP-1 (7-36 amide) (Saxon Biochemicals, Hannover, FRG, 1 pmol x kg(-1) x min(-1)) or placebo (0.9% NaCl with 1% human serum albumin, Behringwerke, Marburg, FRG) were infused intravenously from 22:00 to 7:00 (9 h) and plasma glucose profiles were obtained during the GLP-1 infusion and the following 24 hours. GLP-1 (7-36 amide) (plasma concentration 110 +/- 12 pmol/l) raised plasma C-peptide concentrations (p = 0.0005), suppressed glucagon (p = 0.01) and lowered plasma glucose to 5.5 +/- 0.6 and 6.3 +/- 0.4 mmol/l at 3:00 and 7:00 a.m. (vs. 10.3 +/- 0.9 and 11.3 +/- 0.6 mmol/l, p = 0.0003 and p < 0.0001, respectively, with placebo). Thereafter, starting 1 h after breakfast, no significant differences in plasma glucose, insulin, C-peptide or glucagon profiles were found between experiments with GLP-1 (7-36 amide) and placebo. Average plasma glucose concentrations over the whole 24 h period were reduced by 18% by GLP-1 administered overnight. In conclusion, (1) overnight GLP-1 (7-36 amide) normalizes fasting plasma glucose, but (2) has no sustained effect on meal-induced glucose, insulin or glucagon concentrations once its administration has been stopped. (3) Normalization of fasting plasma glucose alone does not improve daytime metabolic control in NIDDM patients on oral agents.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucagon/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Precursores de Proteínas/uso terapêutico , Idoso , Glicemia/metabolismo , Peptídeo C/sangue , Peptídeo C/efeitos dos fármacos , Esquema de Medicação , Jejum , Feminino , Glucagon/administração & dosagem , Glucagon/sangue , Glucagon/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon , Humanos , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/sangue , Período Pós-Prandial , Precursores de Proteínas/administração & dosagem , Precursores de Proteínas/sangue , Método Simples-Cego , Fatores de Tempo , Resultado do TratamentoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucagon/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Precursores de Proteínas/uso terapêutico , Acarbose , Idoso , Glicemia/metabolismo , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon , Hemoglobinas Glicadas/metabolismo , Humanos , Metformina/uso terapêutico , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Precursores de Proteínas/administração & dosagem , Análise de Regressão , Compostos de Sulfonilureia/uso terapêutico , Trissacarídeos/uso terapêuticoRESUMO
Glucagon-like peptide 1 (GLP-1) is a physiological incretin hormone in normal humans explaining in part the augmented insulin response after oral versus intravenous glucose administration. In addition, GLP-1 also lowers glucagon concentrations, slows gastric emptying, stimulates (pro)insulin biosynthesis, reduces food intake upon intracerebroventricular administration in animals, and may, in addition, enhance insulin sensitivity. Therefore, GLP-1, in many aspects, opposes the Type 2-diabetic phenotype characterized by disturbed glucose-induced insulin secretory capacity, hyperglucagonaemia, moderate insulin deficiency, accelerated gastric emptying, overeating (obesity) and insulin resistance. The other incretin hormone, gastric inhibitory polypeptide (GIP), has lost almost all its activity in Type 2-diabetic patients. In contrast, GLP-1 glucose-dependently stimulates insulin secretion in diet- and sulfonylurea-treated Type 2-diabetic patients and also in patients under insulin therapy long after sulfonylurea secondary failure. Exogenous administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately 3-4 fold physiological postprandial levels fully normalizes fasting hyperglycaemia in Type 2-diabetic patients. The half life of GLP-1 is too short to maintain therapeutic plasma levels for sufficient periods by subcutaneous injections. Current research activities aim at finding GLP-1 analogues with more suitable pharmacokinetic properties than the original peptide. Another approach could be the augmentation of endogenous release of GLP-1, which is abundant in L cells of the lower small intestine and the colon. Interference with sucrose digestion using alpha-glucosidase inhibition moves nutrients into distal parts of the gastrointestinal tract and, thereby, prolongs and augments GLP-1 release. Enprostil, a prostaglandin E2 analogue, fully suppresses GIP responses, while only marginally affecting insulin secretion and glucose tolerance after oral glucose, suggesting compensatory hypersecretion of additional insulinotropic peptides, possibly including GLP-1. Given the large amount of GLP-1 present in L cells, it appears worthwhile to look for more agents that could 'mobilize' this endogenous pool of the 'antidiabetogenic' gut hormone GLP-1.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos/uso terapêutico , Glicemia/metabolismo , Inibidores Enzimáticos/farmacologia , Hormônios Gastrointestinais , Peptídeo 1 Semelhante ao Glucagon , Inibidores de Glicosídeo Hidrolases , Humanos , Peptídeos/metabolismo , Peptídeos/fisiologiaRESUMO
Type 1 diabetes is a disease due to hormone deficiency. Therefore treatment with insulin is hormonal substitution and should be done according to physiological data with 4 injections NPH-insulin and 3 preparandial injections of regular insulin before the main meals. Intensified insulin treatment should be separate substitution of basal and prandial insulin need. The basal insulin substitution should be tested by a fasting day over 24 h giving only basal insulin. Insulin treatment has to be supplemented by diabetes education, blood glucose self control and regulation of diet and exercise. Target values are blood glucose concentrations of 80 to 120 mg/dl fasting and before the main meals, 110 to 160 mg/dl at bedtime and above 65 mg/dl after midnight. A written plan with the algorithms of insulin substitution is helpful for the care of the diabetic patient. A successful insulin treatment is assessed by a HbA1c of 7.x without hypoglycemias.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Insulina/administração & dosagem , Automonitorização da Glicemia , Terapia Combinada , Diabetes Mellitus Tipo 1/sangue , Dieta para Diabéticos , Relação Dose-Resposta a Droga , Esquema de Medicação , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/efeitos adversosAssuntos
Glicemia/metabolismo , Diabetes Mellitus/sangue , Glucagon/farmacologia , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus Tipo 1/sangue , Sistema Digestório/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Digestório , Glucagon/metabolismo , Glucagon/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon , Homeostase , Humanos , Ilhotas Pancreáticas/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Proglucagon , Precursores de Proteínas/metabolismo , Precursores de Proteínas/uso terapêutico , Processamento de Proteína Pós-Traducional , Valores de ReferênciaRESUMO
Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.
Assuntos
Glicemia/metabolismo , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hormônios Gastrointestinais/farmacologia , Glucagon/sangue , Insulina/sangue , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Adulto , Idoso , Peptídeo C/efeitos dos fármacos , Peptídeo C/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 2/fisiopatologia , Jejum/sangue , Jejum/metabolismo , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/fisiologia , Hormônios Gastrointestinais/administração & dosagem , Hormônios Gastrointestinais/efeitos adversos , Hormônios Gastrointestinais/farmacocinética , Glucagon/efeitos dos fármacos , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon , Peptídeos Semelhantes ao Glucagon , Humanos , Injeções Subcutâneas , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/farmacocinética , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peptídeos/farmacocinéticaAssuntos
Diabetes Mellitus Tipo 2/diagnóstico , Hiperlipidemias/diagnóstico , Hipertensão/diagnóstico , Resistência à Insulina/fisiologia , Arteriosclerose/sangue , Arteriosclerose/diagnóstico , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperlipidemias/sangue , Hipertensão/sangue , Lipídeos/sangue , Masculino , Fatores de Risco , SíndromeRESUMO
OBJECTIVE: Glucagon-like peptide I(7-36) amide (GLP-1) is a physiological incretin hormone that, in slightly supraphysiological doses, stimulates insulin secretion, lowers glucagon concentrations, and thereby normalizes elevated fasting plasma glucose concentrations in type II diabetic patients. It is not known whether GLP-1 has effects also in fasting type I diabetic patients. RESEARCH DESIGN AND METHODS: In 11 type I diabetic patients (HbA1c 9.1 +/- 2.1%; normal, 4.2-6.3%), fasting hyperglycemia was provoked by halving their usual evening NPH insulin dose. In random order on two occasions, 1.2 pmol . kg-1 . min-1 GLP-1 or placebo was infused intravenously in the morning (plasma glucose 13.7 +/- 0.9 mmol/l; plasma insulin 26 +/- 4 pmol/l). Glucose (glucose oxidase method), insulin, C-peptide, glucagon, GLP-1, cortisol, growth hormone (immunoassays), triglycerides, cholesterol, and nonesterified fatty acids (enzymatic tests) were measured. RESULTS: Glucagon was reduced from approximately 8 to 4 pmol/l, and plasma glucose was lowered from 13.4 +/- 1.0 to 10.0 +/- 1.2 mmol/l with GLP-1 administration (plasma concentrations approximately 100 pmol, P < 0.0001), but not with placebo (14.2 +/- 0.7 to 13.2 +/- 1.0). Transiently, C-peptide was stimulated from basal 0.09 +/- 0.02 to 0.19 +/- 0.06 nmol/l by GLP-1 (P < 0.0001), but not by placebo (0.07 +/- 0.02 to 0.07 +/- 0.02). There was no significant effect on nonesterified fatty acids (P = 0.34), triglycerides (P = 0.57), cholesterol (P = 0.64), cortisol (P = 0.40), or growth hormone (P = 0.53). CONCLUSIONS: Therefore, exogenous GLP-1 is able to lower fasting glycemia also in type I diabetic patients, mainly by reducing glucagon concentrations. However, this alone is not sufficient to normalize fasting plasma glucose concentrations, as was previously observed in type II diabetic patients, in whom insulin secretion (C-peptide response) was stimulated 20-fold.
Assuntos
Glicemia/metabolismo , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Glucagon/metabolismo , Fragmentos de Peptídeos/farmacologia , Adulto , Análise de Variância , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Jejum , Ácidos Graxos não Esterificados/sangue , Feminino , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon , Peptídeos Semelhantes ao Glucagon , Humanos , Insulina/sangue , Insulina/uso terapêutico , Masculino , Fragmentos de Peptídeos/sangue , Precursores de Proteínas/sangue , Fatores de TempoRESUMO
The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 +/- 6 yr; body mass index, 30.0 +/- 5.2 kg/m2; hemoglobin A1c, 10.5 +/- 1.2%) were studied in the fasting state (plasma glucose, 11.1 +/- 1.1 mmol/L). A liquid meal of 400 mL containing 8% amino acids and 50 g sucrose (327 Kcal) was administered at time zero by a nasogastric tube. Gastric volume was determined by a dye dilution technique using phenol red. In randomized order, GLP-1-(7-36) amide (1.2 pmol/kg.min; Saxon Biochemicals) or placebo (0.9% NaCl with 1% human serum albumin) was infused between -30 and 240 min. In the control experiment, gastric emptying was completed within 120 min, and plasma glucose, insulin, C-peptide, GLP-1-(7-36) amide, and glucagon concentrations transiently increased. With exogenous GLP-1-(7-36) amide (plasma level, approximately 70 pmol/L), gastric volume remained constant over the period it was measured (120 min; P < 0.0001 vs. placebo), and plasma glucose fell to normal fasting values (5.4 +/- 0.7 mmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together with the stimulation of insulin and the inhibition of glucagon secretion, this effect probably contributes to the blood glucose-lowering action of GLP-1-(7-36) amide in type 2-diabetic patients when studied after meal ingestion. At the degree observed, inhibition of gastric emptying, however, must be overcome by tachyphylaxis, reduction in dose, or pharmacological interventions so as not to interfere with the therapeutic use of GLP-1-(7-36) amide in type 2 diabetic patients.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Esvaziamento Gástrico , Glucagon/farmacologia , Insulina/metabolismo , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/farmacologia , Idoso , Feminino , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Precursores de Proteínas/sangueRESUMO
To fate of exogenous glucagon-like peptide I (GLP-I)(7-36) amide was studied in nondiabetic and type II diabetic subjects using a combination of high-pressure liquid chromatography (HPLC), specific radioimmunoassays (RIAs), and a sensitive enzyme-linked immunosorbent assay (ELISA), whereby intact biologically active GLP-I and its metabolites could be determined. After GLP-I administration, the intact peptide could be measured using an NH2-terminally directed RIA or ELISA, while the difference in concentration between these assays and a COOH-terminal-specific RIA allowed determination of NH2-terminally truncated metabolites. Subcutaneous GLP-I was rapidly degraded in a time-dependent manner, forming a metabolite, which co-eluted on HPLC with GLP-I(9-36) amide and had the same immunoreactive profile. Thirty minutes after subcutaneous GLP-I administration to diabetic patients (n = 8), the metabolite accounted for 88.5 +/- 1.9% of the increase in plasma immunoreactivity determined by the COOH-terminal RIA, which was higher than the levels measured in healthy subjects (78.4 +/- 3.2%; n = 8; P < 0.05). Intravenously infused GLP-I was also extensively degraded, but no significant differences were seen between the two groups. Intact GLP-I accounted for only 19.9 +/- 3.4% of the increase in immunoreactivity measured with the COOH-terminal RIA in normal subjects (n = 8), and 25.0 +/- 4.8% of the increase in diabetic subjects (n = 8), the remainder being the NH2-terminally truncated metabolite.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Fragmentos de Peptídeos/metabolismo , Adulto , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Tipo 2/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Glucagon , Peptídeo 1 Semelhante ao Glucagon , Peptídeos Semelhantes ao Glucagon , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacocinética , Radioimunoensaio , Valores de Referência , Sensibilidade e Especificidade , Fatores de TempoRESUMO
The efficacy and tolerability of acarbose was studied in 14 type-2-diabetic patients poorly controlled with diet and sulfonylureas. Acarbose was given in addition to sulfonylureas in a single-blind, placebo-controlled study for three times three months (acarbose-placebo-acarbose). At the beginning of the study and every three months body weight, HbA1c and biochemical and hematological safety parameters were measured. The patients controlled their mid morning urine glucose and two to four times daily their blood glucose concentration with a memory glucometer. Diabetic control improved significantly: HbA1c was 8.5 +/- 1.4% at the beginning, 6.5 +/- 1.1% after three months with acarbose (p < 0.001), 7.2 +/- 0.9% after three months placebo (p < 0.01) and 6.7 +/- 1.3% again after three months with acarbose (p < 0.05). Thus, the effect of acarbose alone accounts for 0.7 or 0.5% respectively, whereas the effect of teaching and diet in a special diabetes unit (the difference from the study to placebo) accounts for 1.3% of HbA1c. Home monitored blood and urine glucose values were improved: The postprandial blood glucose concentrations, the postprandial differences, the mean blood glucose concentrations and the glycosuria were decreased during acarbose treatment in comparison with placebo. The preprandial blood glucose concentrations before breakfast and supper were not influenced by acarbose. Hematological and biochemical safety parameters as well as blood pressure and heart rate were unchanged. Meteorism and flatulence as typical side effects decreased during treatment. Acarbose is a safe and effective adjunct treatment for type-2-diabetic patients uncontrolled with diet and sulfonylurea alone.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glibureto/administração & dosagem , Hipoglicemiantes/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Trissacarídeos/administração & dosagem , Acarbose , Glicemia/metabolismo , Terapia Combinada , Diabetes Mellitus Tipo 2/sangue , Dieta para Diabéticos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Glibureto/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Trissacarídeos/efeitos adversosRESUMO
Fifty-two patients and 36 controls were compared in a search for insulin gene variants among type II diabetic patients with fasting hyperinsulinemia (above 90 microU/ml) and a fasting C-peptide to insulin molar ratio between 1.11 and 1.50. Alpha and beta alleles of the insulin gene were characterized by restriction analysis of polymerase chain reaction (PCR) products and direct sequencing. The more frequent occurrence of the alpha allele of the insulin gene within the control population as compared with a prevalence of the beta allele in the diabetic patients (P, 0.05) was observed. The beta allele, usually described as the rare allele, seems to be associated with the disease.
Assuntos
Alelos , Diabetes Mellitus Tipo 2/genética , Insulina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Peptídeo C/metabolismo , DNA , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Frequência do Gene , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da PolimeraseRESUMO
Glucagon-like peptide 1 (GLP-1) (7-36 amide) is a physiological incretin hormone that is released after nutrient intake from the lower gut and stimulates insulin secretion at elevated plasma glucose concentrations. Previous work has shown that even in Type 2 (non-insulin-dependent) diabetic patients GLP-1 (7-36 amide) retains much of its insulinotropic action. However, it is not known whether the magnitude of this response is sufficient to normalize plasma glucose in Type 2 diabetic patients with poor metabolic control. Therefore, in 10 Type 2 diabetic patients with unsatisfactory metabolic control (HbA1c 11.6 +/- 1.7%) on diet and sulphonylurea therapy (in some patients supplemented by metformin or acarbose), 1.2 pmol x kg-1 x min-1 GLP-1 (7-36 amide) or placebo was infused intravenously in the fasting state (plasma glucose 13.1 +/- 0.6 mmol/l). In all patients, insulin (by 17.4 +/- 4.7 nmol x 1-1 x min; p = 0.0157) and C-peptide (by 228.0 +/- 39.1 nmol x 1-1 x min; p = 0.0019) increased significantly over basal levels, glucagon was reduced (by -1418 +/- 308 pmol x 1-1 x min) and plasma glucose reached normal fasting concentrations (4.9 +/- 0.3 mmol/l) within 4 h of GLP-1 (7-36 amide) administration, but not with placebo. When normal fasting plasma glucose concentrations were reached insulin returned towards basal levels and plasma glucose concentrations remained stable despite the ongoing infusion of GLP-1 (7-36 amide). Therefore, exogenous GLP-1 (7-36 amide) is an effective means of normalizing fasting plasma glucose concentrations in poorly-controlled Type 2 diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Hiperglicemia/sangue , Fragmentos de Peptídeos/farmacologia , Adulto , Jejum , Feminino , Glucagon , Peptídeo 1 Semelhante ao Glucagon , Peptídeos Semelhantes ao Glucagon , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Infusões Intravenosas , Cinética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fatores de TempoRESUMO
The hypoglycemic effect of alcohol, probably caused by inhibition of gluconeogenesis in the liver, is well known. However, accurate data on the effect of usual amounts of alcohol on the blood sugar in type 1 diabetics are not available. We therefore investigated the effect of an evening dose of alcohol on the blood sugar in 23 male type 1 diabetics (age 32.8 [20 to 64] years, duration of diabetes 11.5 [0.5 to 38] years, Broca index 0.98 [0.83 to 1.34] HbAlc 8.4 [5.8 to 12.2]%). On one day, the diabetics were given 0.56 g ethanol per kg body weight to drink in the evening, corresponding to about one liter of diabetic beer, on another day, the same volume of mineral water. In addition, eleven of the 23 patients received half the amount of alcohol on a third evening. Between 7 and 11 o'clock in the morning after alcohol consumption, blood glucose levels were significantly lower. The number of hypoglycemic episodes in the morning of the day following alcohol administration was appreciably greater. Usual amounts of alcohol consumed after the evening meal thus increase the risk of hypoglycemia the following morning. Diabetics should be instructed accordingly.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Hipoglicemia/sangue , Adulto , Consumo de Bebidas Alcoólicas/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Slowly resorbable carbohydrates are preferred in the dietetic therapy of patients with type 2 diabetes. In this study we compared the efficacy of a "müsli" with the alpha-glucosidase inhibitor miglitol in delaying the resorption of carbohydrates. 24 patients with NIDDM took, in randomized order, four different breakfasts with equal amounts of carbohydrate: a standard breakfast with bread and marmelade, a müsli, and both breakfasts with 100 mg miglitol. We calculated the maximal blood glucose concentration, the postprandial difference, the time of the maximum and the area under the curve (AUC). The postprandial blood glucose increase after the müsli breakfast was significantly lower compared with the standard breakfast (maximal blood glucose 12.3 vs. 13.9 mmol/l, postprandial difference 3.6 vs. 5.1 mml/l, AUC 360 vs, 468 mmol/l x min). The blood glucose increase after the standard breakfast with miglitol was even lower (maximum 11.6 mmol/l, postprandial difference 2.9 mmol/l, AUC 241 mmol/l x min). Miglitol also lowered the blood glucose values after the müsli breakfast. This study shows that the alpha-glucosidase inhibitor miglitol in a dose of 100 mg is more effective in lowering the postprandial blood glucose increase than a müsli. In cases of non-acceptance of a modern diet with slowly resorbable carbohydrates, alpha-glucosidase inhibitors may be a therapeutic alternative.
Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Carboidratos da Dieta/metabolismo , Absorção Intestinal/efeitos dos fármacos , 1-Desoxinojirimicina/análogos & derivados , Adulto , Idoso , Glicemia/análise , Dieta para Diabéticos , Fibras na Dieta/farmacologia , Glucosamina/análogos & derivados , Glucosamina/farmacologia , Inibidores de Glicosídeo Hidrolases , Humanos , Imino Piranoses , Pessoa de Meia-IdadeRESUMO
Measurement of protein glycation (fructosamine) has become an accepted tool in diabetes diagnostics. Among different methods available, the serum fructosamine test published by Johnson and Baker in 1983 has gained wide acceptance due to a simple and easily automated assay procedure providing clinically meaningful results. A recent modification of the Nitroblue Tetrazolium (NBT) reagent, improved by addition of tensides and uricase, exhibits lower interference by lipaemia and urate. It is also less affected by the sample matrix and yields results closer to the physiological range of glycated proteins. Furthermore, a completely new standardization protocol was used in the preparation of calibration material. The new colorimetric method for the determination of fructosamine was evaluated in 12 European clinical laboratories.
Assuntos
Diabetes Mellitus/diagnóstico , Glicoproteínas , Hexosaminas/sangue , Glicemia/metabolismo , Proteínas Sanguíneas/metabolismo , Diabetes Mellitus/sangue , Seguimentos , Frutosamina , Hemoglobinas Glicadas/metabolismo , Humanos , Proteínas Séricas GlicadasRESUMO
Daily profiles of blood glucose, HbA1c, total protein and fructosamine were measured in 10 diabetic patients and the factor fructosamine x 7/g total protein was calculated. Measurements were done at 4 a.m. to be sure that the patients were sleeping for some time, during the day and the following evening at 11 p.m., when the patients were lying again, so that the influence of orthostasis, the difference between bed rest and walking could be demonstrated. The blood glucose profile was typical whereas the HbA1c concentration was very stable and constant. Total protein and fructosamine increased significantly by orthostasis; the correction of fructosamine by total protein diminished the differences, but did not completely eliminate the effect of orthostasis. However, fructosamine should be corrected by the total protein concentration in order to increase the diagnostic value of the parameter.