RESUMEN
Although the hereditary nature of non-insulin-dependent diabetes mellitus (NIDDM) is well recognized, the nature of the predisposing defect remains elusive. Individuals with a history of gestational diabetes had shown a reduced insulin-sensitivity index (S1) in the absence of fasting hyperglycemia. To determine whether this finding could result from an inherited defect of the insulin receptor, an NIDDM pedigree was ascertained through a former gestational-diabetic proband. The proband, her siblings, and her first cousins were clinically characterized for insulin sensitivity with the minimal-model-based S1 from a modified glucose tolerance test. Islet function was characterized by the incremental insulin response to 5 g i.v. arginine at baseline and at a plasma glucose level of 500-600 mg/dl. Genetic studies included linkage analyses for the insulin gene and the insulin-receptor gene with DNA polymorphisms (restriction-fragment-length polymorphisms, RFLPs) previously described. The pattern of inheritance in this large pedigree appeared to follow autosomal-dominant transmission. No defect in islet function was found, but as a group, third-generation family members had an S1 that was significantly lower than that of weight-matched control individuals, suggesting an inherited defect in insulin action. Genetic studies showed no sharing of insulin gene, insulin-receptor-gene alleles among the diabetic individuals, or insulin-receptor alleles among third-generation individuals with insulin insensitivity. The genetic analyses thus suggest that this pedigree has an inherited defect that is not linked to the insulin gene or the insulin-receptor gene. The diminished S1 may nonetheless suggest an inherited defect in insulin action.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Ligamiento Genético , Insulina/genética , Islotes Pancreáticos/metabolismo , Embarazo en Diabéticas , Receptor de Insulina/genética , Adulto , Alelos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/transmisión , Femenino , Regulación de la Expresión Génica , Haplotipos , Humanos , Resistencia a la Insulina , Masculino , Linaje , Embarazo , Embarazo en Diabéticas/sangreRESUMEN
Although the minimal-model-based insulin sensitivity index (S1) can be estimated from the results of a simple 180-min intravenous glucose tolerance test (IVGTT), its relationship to widely accepted but technically more difficult clamp-based techniques has not been resolved in humans. Therefore we measured S1 by standard IVGTT, modified IVGTT, and clamp methods in 10 nondiabetic men with %IBW of 109 +/- 12 (mean +/- SD). In the euglycemic clamp studies, insulin was infused to bring insulin levels (IRI) from basal, 8 +/- 4 microU/ml, to plateaus of 21 +/- 5 and 35 +/- 6 microU/ml. S1[clamp], measured as the increase in glucose (G) clearance per increase in IRI [delta INF/(delta IRI X G)], averaged 0.29 +/- 0.09 ml/kg X min per microU/ml. In the IVGTT studies, 300 mg/kg G was given as an i.v. bolus, and G and IRI were measured for 180 min; in the modified (mod) IVGTT, tolbutamide (300-500 mg) was given i.v. 20 min after the G to observe the effect of an IRI peak on G removal after G level was free of initial "mixing" effects. The S1 estimated by computer did not differ significantly between standard [(6.9 +/- 3.4) X 10(-4) min-1 per microU/ml] and modified [(6.7 +/- 3.5) X 10(-4) min-1 per microU/ml] tests, indicating no bias due to the differing insulin patterns and levels. There was a strong positive correlation between S1 (mod IVGTT) and S1(clamp): r = 0.84; N = 10; P less than 0.002. The correlation between S1(standard IVGTT) and S1(clamp) was 0.54, suggesting the modified test is less "noisy." Nonetheless, in eight euglycemic women with a wider range of adiposity, S1(standard IVGTT) has been significantly correlated with %IBW (r = -0.72) and basal IRI (r = -0.84). The correlation between S1 measures by clamp and IVGTT methods provides one step toward validation of the minimal model for studies of insulin action in man.
Asunto(s)
Prueba de Tolerancia a la Glucosa , Insulina/farmacología , Adulto , Animales , Glucemia/análisis , Perros , Glucosa/farmacología , Humanos , Insulina/sangre , Insulina/metabolismo , Masculino , Tolbutamida/farmacologíaRESUMEN
To determine which test of islet function is the most sensitive indicator of subclinical beta-cell loss, we studied six conscious dogs before and 1 and 6 wk after removal of the splenic and uncinate lobes [64 +/- 2% pancreatectomy (PX)]. To assess hyperglycemic potentiation, acute insulin secretory responses (AIR) to 5 g i.v. arginine were measured at the fasting plasma glucose (FPG) level after PG was clamped at approximately 250 mg/dl and after PG was clamped at a maximally potentiating level of 550-650 mg/dl. FPG levels were unaffected by PX (112 +/- 4 mg/dl pre-PX vs. 115 +/- 5 mg/dl 6 wk after PX, P NS). Similarly, basal insulin levels remained constant after PX (11 +/- 2 microU/ml pre-PX vs. 11 +/- 1 microU/ml 6 wk after PX, P NS). The AIR to 300 mg/kg i.v. glucose decreased slightly from 42 +/- 9 microU/ml pre-PX to 32 +/- 5 microU/ml 6 wk after PX (P NS), and thus the beta-cell loss was underestimated. In contrast, insulin responses to arginine declined markedly after PX. The AIR to arginine obtained at FPG levels declined from 23 +/- 3 microU/ml pre-PX to 13 +/- 2 microU/ml 6 wk after PX (P = .04). The AIR to arginine obtained at PG levels of approximately 250 mg/dl declined even more, from a pre-PX value of 56 +/- 7 microU/ml to 21 +/- 4 microU/ml 6 wk after PX (P = .02).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glucemia/metabolismo , Islotes Pancreáticos/fisiología , Animales , Arginina , Catecolaminas/sangre , Perros , Glucagón/metabolismo , Glucosa , Insulina/sangre , Insulina/metabolismo , Insulina/fisiología , Secreción de Insulina , Masculino , PancreatectomíaRESUMEN
NIDDM is characterized by decreased insulin secretory responses to glucose and to nonglucose stimuli, hyperglucagonemia, and decreased tissue sensitivity to insulin. However, it has been unclear which of these abnormalities, if any, precedes the others. Since women with histories of gestational diabetes mellitus (GDM) are at high risk for eventual development of NIDDM, we measured B- and A-cell function and tissue sensitivity to insulin in eight normoglycemic, postpartum women with recent histories of GDM and in eight control subjects pair-matched for age and percent of ideal body weight. Fasting plasma glucose levels in subjects with former GDM tended to be slightly higher than in matched controls (98 +/- 3 versus 92 +/- 2 mg/dl, P = 0.07). Basal plasma insulin in subjects with former GDM was significantly higher than in controls (22 +/- 4 versus 14 +/- 2 microU/ml, P = 0.05). During an intravenous glucose tolerance test (IVGTT), relative first- and second-phase insulin responses to glucose were decreased in subjects with former GDM (2316 +/- 560 versus 7798 +/- 1036% of basal X min, P = 0.004; and 8340 +/- 946 versus 14,509 +/- 2556, P = 0.04). An index of sensitivity to insulin, SI, calculated from the IVGTT, was also lower in former GDM (1.23 +/- 0.69 X 10(-4) versus 3.58 +/- 0.78 X 10(-4) min-1/microU/ml, P = 0.001). Acute insulin responses to 5 g i.v. arginine were measured at plasma glucose levels of approximately 95, 215, and 600 mg/dl. The response at 600 mg/dl is termed the AIRmax and is used as an index of glucose-regulated insulin secretory capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Arginina/farmacología , Resistencia a la Insulina , Insulina/metabolismo , Embarazo en Diabéticas/metabolismo , Adulto , Glucemia/análisis , Diabetes Mellitus/sangre , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/sangre , Femenino , Glucagón/sangre , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Secreción de Insulina , Norepinefrina/sangre , Obesidad , EmbarazoRESUMEN
Nondiabetic, HLA-identical siblings of insulin-dependent diabetic subjects have an increased risk of developing diabetes. Since insulin resistance is present in newly diagnosed diabetic subjects, we studied 12 HLA-identical siblings to determine whether they have impaired insulin sensitivity. Each sibling was carefully matched for age, sex, and body weight to a control from a nondiabetic family. The insulin sensitivity index (SI) was determined after an intravenous glucose tolerance test (IVGTT) using the minimal model of insulin kinetics. The insulin sensitivity index was significantly lower in the HLA-identical siblings compared with their matched controls.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Antígenos HLA/análisis , Resistencia a la Insulina , Adolescente , Adulto , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , MasculinoRESUMEN
To determine the effect of tolbutamide on insulin release to nonglucose stimuli in non-insulin-dependent diabetes mellitus and how plasma glucose levels may modulate this effect, the acute insulin response (AIR) to an isoproterenol (12 Micrograms) or an arginine (5 g) i.v. pulse was determined before and during a tolbutamide infusion (7.5 mg/m2/min) in 25 male subjects. During the tolbutamide infusion, there was an increase in the AIR to both isoproterenol (% delta AIR = +49 +/- 21%, N = 11, P less than 0.05) and arginine (% delta AIR = +52 +/- 15%, N = 12, P less than 0.005) and a decrease in plasma glucose (delta plasma glucose for isoproterenol = -24 +/- 6 mg/dl, P less than 0.005; for arginine = -26 +/- 3 mg/dl, P less than 0.001). In separate studies, when the plasma glucose was clamped at baseline values by a variable rate of glucose infusion, there was a greater effect of tolbutamide on AIR when compared with the unclamped tolbutamide studies (isoproterenol: % delta AIR = +132 +/- 25%, P less than 0.025; arginine: % delta AIR = +95 +/- 12%, P less than 0.05). Thus, tolbutamide increases the AIR of nonglucose stimuli, but this augmentation by tolbutamide is blunted by the concomitant decrease in plasma glucose. Consideration of this observation is necessary when interpretating the effects of a sulfonylurea on islet cell responses.
Asunto(s)
Arginina/farmacología , Diabetes Mellitus/metabolismo , Insulina/metabolismo , Isoproterenol/farmacología , Tolbutamida/farmacología , Adulto , Anciano , Glucemia/metabolismo , Glucosa/farmacología , Humanos , Secreción de Insulina , Masculino , Persona de Mediana EdadRESUMEN
In 20 patients with untreated non-insulin-dependent diabetes mellitus (NIDDM), there was a positive relationship between fasting plasma glucose (FPG) and glucose production rate, calculated by the isotope dilution technique (r = 0.72, P less than 0.001). This suggests that glucose production rate is an important determinant of FPG in untreated NIDDM. Fifteen patients were also studied during therapy with chlorpropamide for 3-6 mo. During therapy, FPG was lower (133 +/- 9 vs. 216 +/- 20 mg/dl, mean +/- SEM; P less than 0.001), glucose production was lower (59.5 +/- 2.0 vs 77.6 +/- 4.9 mg/m2/min; P less than 0.005), and there was a significant correlation between the fall in glucose production and the fall in FPG (r = 0.59, P less than 0.05). Fasting IRI levels increased in some, but not all, patients during chlorpropamide (untreated 18 +/- 2, treated 21 +/- 2 muU/ml; P= NS). However, there was a significant relationship between the percent rise in IRI and the fall in glucose production during treatment (r = 0.75, P less than 0.001). Patients with a rise in fasting insulin during therapy had a greater fall in glucose production than those whose insulin did not rise (25.4 +/- 8.1 vs. 7.8 +/- 2.4 mg/m2/min; P less than 0.005). When a low-dose insulin infusion was given to approximate the increases of portal venous insulin during therapy, similar falls of glucose production occurred. We conclude that inhibition of endogenous glucose production during chronic chlorpropamide therapy is an important mechanism for the lowering of FPG and that enhanced insulin secretion is the reason for the major part of this inhibition. The small fall in glucose production in those patients whose insulin level did not rise during therapy suggests an additional contribution by some other mechanism.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Glucosa/biosíntesis , Hígado/metabolismo , Compuestos de Sulfonilurea/uso terapéutico , Adulto , Anciano , Glucemia/análisis , Clorpropamida/uso terapéutico , Femenino , Humanos , Hiperglucemia/fisiopatología , Insulina/farmacología , Hígado/efectos de los fármacos , Masculino , Persona de Mediana EdadRESUMEN
To assess the relationship between beta-cell function and the level and duration of hyperglycemia during generalized beta-cell impairment, we studied the effects of acute and prolonged infusion of somatostatin in seven normal men. Twenty minutes after beginning an acute infusion of somatostatin (200 microgram/h) plus glucagon replacement (0.75 ng/kg/min), plasma glucose (PG) remained unchanged, but plasma insulin (IRI) and acute insulin response to isoproterenol had fallen markedly. Seventy minutes after beginning somatostatin-plus-glucagon, a rise in PG was associated with an increase in the acute insulin response to isoproterenol, though not to the control level. In a separate study, after 46 h of the somatostatin-plus-glucagon infusion, at a glucose level similar to the 70-min level, plasma insulin had returned nearly to the control level and the acute insulin response to isoproterenol had returned completely to the control level. Such increases inb basal and stimulated insulin secretion most likely represent a time-dependent adaptation by the beta-cells to the persistent hyperglycemia. First- and second-phase insulin responses to intravenous glucose were markedly inhibited after 46 h of somatostatin-plus-glucagon. In summary, a 46-h infusion of somatostatin with glucagon replacement in humans leads to hyperglycemia, a slightly diminished basal insulin level, markedly decreased insulin responses to glucose, and an insulin response to isoproterenol maintained at a normal level by acute and probably chronic adaptation to the hyperglycemia. We speculate that beta-cell adaptation to hyperglycemia may explain the similar abnormalities of islet function observed in patients with NIDDM.
Asunto(s)
Hiperglucemia/fisiopatología , Islotes Pancreáticos/fisiología , Somatostatina/farmacología , Adaptación Fisiológica , Adolescente , Adulto , Glucemia , Glucagón/farmacología , Glucosa , Humanos , Insulina/sangre , Isoproterenol/farmacología , Masculino , Factores de TiempoRESUMEN
Insulin secretion and insulin sensitivity were compared in 12 HLA-identical siblings of insulin-dependent diabetics and nondiabetic controls. Only the maximum acute insulin response to intravenous arginine was lower in the siblings than in the matched controls (P less than .05); other measures of insulin secretion, including the acute insulin response to glucose or arginine, the second-phase insulin response to glucose, and the slope of glucose potentiation, were not significantly different. Insulin sensitivity, derived from an intravenous glucose tolerance test with a minimal-modeling technique, was lower in the siblings (P less than .01). In a large group of nondiabetic controls of various adiposity, insulin secretion and insulin sensitivity were inversely related. In view of the difference in insulin sensitivity between siblings and matched controls, a direct comparison of beta-cell function tests may be inappropriate, and the measures of insulin secretion were compared with those of nondiabetics when adjusted for differences in insulin sensitivity. This analysis revealed that all measures of insulin secretion were significantly lower in the siblings. We conclude that HLA-identical siblings of insulin-dependent diabetics show evidence of both insulin resistance and impaired beta-cell function and that analysis of beta-cell function in relation to insulin sensitivity shows a greater frequency of beta-cell secretory abnormalities than previously appreciated.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Antígenos HLA/análisis , Resistencia a la Insulina/genética , Islotes Pancreáticos/metabolismo , Adulto , Arginina , Glucemia/análisis , Diabetes Mellitus Tipo 1/inmunología , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Islotes Pancreáticos/efectos de los fármacos , Estadística como AsuntoRESUMEN
To determine whether prolonged nicotinic acid (NA) administration produces insulin resistance and, if so, how the normal pancreatic islet adapts to prolonged insulin resistance, we administered incremental doses of NA to 11 normal men for 2 wk, ending at 2 g/day. Insulin sensitivity was measured with Bergman's minimal model. Islet function was evaluated by measurement of acute insulin (AIR) and glucagon (AGR) responses to arginine at three glucose levels. Insulin resistance was demonstrated and quantified by a marked drop in the insulin sensitivity index (Sl) from 6.72 +/- 0.77 to 2.47 +/- 0.36 x 10(-5) min-1/pM (P less than .0001) and resulted in a doubling of basal immunoreactive insulin levels (from 75 +/- 7 to 157 +/- 21 pM, P less than .001) with no change in fasting glucose (5.5 +/- 0.1 vs. 5.7 +/- 0.1 mM). Proinsulin levels also increased (from 9 +/- 1 to 15 +/- 2 pM, P less than .005), but the ratio of proinsulin to immunoreactive insulin did not change (12.7 +/- 1.9 vs. 10.3 +/- 1.9%). beta-Cell changes were characterized by increases in the AIR to glucose (from 548 +/- 157 to 829 +/- 157 pM, P less than .005) and in the AIR to arginine at the fasting glucose level (from 431 +/- 54 to 788 +/- 164 pM, P less than .05). At the maximal hyperglycemia level the AIR to arginine represents beta-cell secretory capacity, and this increased with administration of NA (from 2062 +/- 267 to 2630 +/- 363 pM, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Resistencia a la Insulina , Islotes Pancreáticos/metabolismo , Ácidos Nicotínicos/farmacología , Adulto , Glucemia/análisis , Epinefrina/sangre , Glucagón/sangre , Glucagón/metabolismo , Humanos , Hidrocortisona/sangre , Inyecciones Intravenosas , Islotes Pancreáticos/efectos de los fármacos , Masculino , Norepinefrina/sangreRESUMEN
Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18-44 years of age; body mass index, 19.5-52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated beta-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG - [SI x basal insulin]). Insulin-dependent glucose uptake was estimated as SI x IIR0-19, because the relationship between SI and beta-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI x IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glucemia/metabolismo , Prueba de Tolerancia a la Glucosa , Insulina/fisiología , Islotes Pancreáticos/metabolismo , Adulto , Índice de Masa Corporal , Femenino , Humanos , Insulina/metabolismo , Secreción de Insulina , Masculino , Modelos Biológicos , Valores de Referencia , Análisis de Regresión , Factores SexualesRESUMEN
To determine the relationship between insulin sensitivity and beta-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18-44 yr of age; body mass index 19.5-52.2 kg/m2) and with fasting glucose levels < 6.4 mM. SI was compared with measures of body adiposity and beta-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the beta-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and beta-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the beta-cell measures could not be distinguished from a hyperbola, i.e., SI x beta-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, beta-cell function varies quantitatively with differences in insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Resistencia a la Insulina/fisiología , Islotes Pancreáticos/citología , Islotes Pancreáticos/fisiología , Tejido Adiposo/citología , Tejido Adiposo/fisiología , Adolescente , Adulto , Composición Corporal/fisiología , Estatura/fisiología , Índice de Masa Corporal , Peso Corporal/fisiología , Femenino , Humanos , Insulina/farmacología , Masculino , Obesidad/patología , Obesidad/fisiopatología , Estadística como AsuntoRESUMEN
To determine whether exercise-induced increases in tissue plasminogen activator (t-PA) were related to plasma epinephrine concentration during exercise, 14 healthy men (aged 24 to 62 years) were studied during epinephrine infusions (10, 25 and 50 ng/kg per min) and graded supine bicycle exercise, beginning at 33 W and increasing in 33-W increments until exhaustion. Plasma epinephrine, active and total t-PA, active plasminogen activator inhibitor type 1 (PAI-1) and t-PA/PAI-1 complex concentrations were measured at each exercise and infusion level. During epinephrine infusion, active and total t-PA levels increased linearly with the plasma epinephrine concentration (respective slopes [+/- SEM] of 0.062 +/- 0.003 and 0.076 +/- 0.003 pmol/ng epinephrine). During exercise, t-PA levels did not increase until plasma epinephrine levels increased, after which both active and total t-PA levels again increased linearly with the plasma epinephrine concentration, but at twice the rate observed with epinephrine infusion (0.131 +/- 0.005 and 0.147 +/- 0.005 pmol/ng, respectively). The t-PA level in blood was directly proportional to the plasma epinephrine concentration during both exercise and epinephrine infusion, suggesting that epinephrine release during exercise stimulates t-PA secretion. In these healthy subjects, active plasminogen activator inhibitor type 1 and t-PA/PAI-1 complex levels were low (41 +/- 11 and 21 +/- 5 pmol/liter, respectively) and did not change significantly during exercise or epinephrine infusion. It is concluded that approximately 50% of the increase in t-PA during exercise is due to stimulated release of t-PA by epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Epinefrina/farmacología , Ejercicio Físico/fisiología , Fibrinólisis/fisiología , Activador de Tejido Plasminógeno/sangre , Adulto , Epinefrina/sangre , Prueba de Esfuerzo , Humanos , Masculino , Inactivadores Plasminogénicos/sangreRESUMEN
It is not clear whether diabetic patients can learn accurate self-monitoring of blood glucose (SMBG) by use of written package instructions. In addition, it is unclear whether the improvement in accuracy of monitoring that results from professional training is due to the professional intervention or to a personal practice effect. For these reasons, improvement in accuracy of SMBG (using Chemstrip bG, Biodynamics Division, Boehringer-Mannheim, Indianapolis, Indiana) after a 30-min session of professional instruction in one group of diabetic patients was compared with improvement after 30 min of practice and study of package instructions in another group. After initial reading of package instructions in both groups, and after the practice session in the control group, mean percent error was 22-37%. In contrast, mean percent error declined to 9% after a professional training session. We conclude that learning SMBG solely by reading package instructions leads to unacceptable inaccuracy. However, by use of short, intensive instruction sessions, a diabetes educator can reduce such errors and teach highly accurate monitoring to most diabetic patients.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus/sangre , Educación del Paciente como Asunto , Autocuidado , Adulto , Anciano , Estudios de Evaluación como Asunto , Humanos , Masculino , Persona de Mediana Edad , Monitoreo FisiológicoRESUMEN
The pathogenesis of the abnormal metabolic state in patients with non-insulin-dependent diabetes (NIDDM) is controversial. Even the term NIDDM stirs controversy because of the easily drawn inference that individuals with this form of diabetes do not need insulin treatment. Yet many patients with NIDDM are treated with insulin; some even develop hyperosmolar coma if not given insulin. Ketoacidosis, however, is very infrequent in this syndrome, implying that these patients are not dependent on insulin treatment to prevent mass mobilization of fatty acids and ketone bodies. The phrase noninsulin-dependent is therefore appropriate when used in this restricted fashion but inappropriate when used to imply adequacy of insulin secretion. The evaluation of the adequacy of islet function in this syndrome has been complex, since there is no standard of insulin output that can be defined for normal islets without specifying the physiologic setting under which the assessment has been made. For example, individuals with normal glucose levels but variable degrees of obesity have widely varying insulin secretion rates. Thus, the choice of controls is critical when comparing islet function in NIDDM to normal. In addition, the efficiency of the B-cell response to a challenge (e.g., oral glucose tolerance test) can markedly influence the magnitude of the stimulatory glucose level during the period of testing. For example, a subject with some impairment of insulin output will tend to become more hyperglycemic during the test. The hyperglycemia may then stimulate more insulin secretion so that the overall insulin output may appear equal to or even greater than that of a normal individual. In such a closed-loop system, strict control of input variables is necessary to evaluate whether or not insulin secretion is normal. As will be discussed, control of glucose level and other variables is seldom accomplished in dynamic glucose tolerance tests. As will be presented in this review, the development of appropriately controlled studies of islet function has provided convincing evidence that islet B-cell function is abnormal in patients with NIDDM. Since these studies are based on an understanding of normal islet function, normal islet B-cell physiology is discussed before pathophysiology. Finally, the implications of this analysis for the treatment of NIDDM with diet, hypoglycemic sulfonylureas, and insulin will be discussed.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Administración Oral , Animales , Glucemia/análisis , Diabetes Mellitus/terapia , Diabetes Mellitus Tipo 2/terapia , Ayuno , Glucosa/administración & dosificación , Prueba de Tolerancia a la Glucosa , Humanos , Infusiones Parenterales , Insulina/genética , Secreción de Insulina , Obesidad , Proinsulina/análisis , Ratas , Receptores Adrenérgicos alfa/fisiologíaRESUMEN
The pancreatic islet can be viewed as an integrator of nutrient, neural, and hormonal signals. In normal people, glucose directly stimulates insulin release and also plays a key role as a potentiator of nonglucose stimulants of the B-cells. In patients with non-insulin-dependent diabetes mellitus (NIDDM), the direct effect of glucose on insulin secretion is markedly impaired. However, as hyperglycemia develops, basal insulin levels and insulin responses to nonglucose signals are maintained in many NIDD patients by the potentiating effect of hyperglycemia. Both acute and chronic administration of sulfonylurea drugs results in enhanced B-cell sensitivity to the potentiating effect of glucose. During sulfonylurea therapy this effect initially causes an increase in insulin level. However, as the glucose level falls during therapy the insulin level may tend to return toward pretreatment values, thereby masking the improvement of B-cell function. In NIDD patients with mild to moderate hyperglycemia (fasting plasma glucose less than 200 mg/dl), chronic sulfonylurea therapy results in the maintenance of near-normal insulin levels, but at a lower plasma glucose level. In patients with more severely impaired B-cell function, whose insulin levels before therapy are subnormal despite marked hyperglycemia, there is a net absolute increase in insulin levels during chronic sulfonylurea administration. Thus, some NIDD patients may show an increase in basal insulin levels during chronic sulfonylurea therapy while others may not; however, all patients who respond to sulfonylureas demonstrate increased B-cell sensitivity to glucose. Acute and chronic sulfonylurea treatment also results in a suppression of glucagon levels, an effect that may be secondary to the enhancement of B-cell function. The fall of plasma glucose during chronic sulfonylurea therapy is associated with a decrease in hepatic glucose production in NIDD patients. The magnitude of this effect is correlated with the degree of enhancement of basal insulin secretion. Thus, chronic sulfonylurea therapy clearly enhances pancreatic islet function in patients with NIDDM. We postulate that the major antihyperglycemic action of sulfonylurea therapy is mediated by this pancreatic effect.
Asunto(s)
Hipoglucemiantes/farmacología , Islotes Pancreáticos/efectos de los fármacos , Compuestos de Sulfonilurea/farmacología , Clorpropamida/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Retroalimentación , Glucagón/metabolismo , Glucosa/farmacología , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Secreción de Insulina , Hígado/efectos de los fármacos , Hígado/metabolismo , Compuestos de Sulfonilurea/uso terapéutico , Factores de Tiempo , Tolbutamida/farmacologíaRESUMEN
Immunoreactive insulin responses to a 20-g iv glucose challenge during a 7.5 mg/m2/min tolbutamide infusion were studied in 21 untreated noninsulin-dependent male diabetics. All data were analyzed by paired t tests. During the tolbutamide infusion, compared to the saline control period in the same subjects, glucose levels were lowered [217 +/- 17 vs. 196 +/- 16 mg/dl (mean +/- SEM); P less than 0.005], and there was an increase in both first phase (2 +/- 1 vs. 16 +/- 4 micro U/ml; P less than 0.005) and second phase insulin responses (296 +/- 71 vs. 499 +/- 101 micro U. min/ml; P less than 0.05; n = 21). However, when the prestimulus glucose level was lowered by an insulin infusion (214 +/- 20 vs. 145 +/- 17 mg/dl; P less than 0.001), no effect on first phase insulin secretion was observed, and the second phase response decreased (290 +/- 78 vs. 124 +/ 55 micro U. min/ml; P less than 0.005; n = 11; saline control vs. insulin infusion). In 8 subjects, the plasma glucose level during the tolbutamide infusion was kept constant by a concurrent variable glucose infusion. First phase insulin secretion was still increased, though no more than in studies were plasma glucose was not kept constant. However, there was further augmentation of the second phase response (tolbutamide alone, 443 +/- 142 micro U. min/ml; tolbutamide plus glucose, 802 +/- 232 micro U. min/ml; P less than 0.05). These findings indicate that tolbutamide augments first phase insulin secretion in untreated diabetics independently of the prestimulus glucose level. However, changes in the glucose level significantly modulate the sulfonylurea influence on the second phase insulin response to glucose. This effect of glucose level is an important consideration when evaluating the insulinotropic effects of a sulfonylurea.
Asunto(s)
Diabetes Mellitus/metabolismo , Glucosa , Insulina/metabolismo , Tolbutamida/uso terapéutico , Adulto , Anciano , Glucemia/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Humanos , Secreción de Insulina , Masculino , Persona de Mediana EdadRESUMEN
Although obese women with histories of gestational diabetes mellitus (former GDM) are highly predisposed to develop noninsulin-dependent diabetes mellitus (NIDDM), lean former GDM women are less predisposed. To explore reasons for this difference, we performed measures of islet B-cell function and insulin action in eight lean former GDM women [ideal body weight (IBW), 107 +/- 2% (mean +/- SEM)], 11 obese former GDM (IBW, 161 +/- 11%), and 19 normal women subjects who were individually pair-matched to former GDM for % IBW and age. The first phase (0-10 min) insulin secretory response to iv glucose was significantly lower in both lean and obese former GDM compared to that in normal women (3,480 +/- 548% vs. 8,234 +/- 1,337% basal . min and 3,444 +/- 682 vs. 10,251 +/- 2,465). The second phase (10-60 min) insulin response to glucose was also significantly lower in lean former GDM women and tended to be lower in obese former GDM women compared to that in their respective controls. Insulin action was assessed by the insulin sensitivity index (SI) using Bergman's minimal modeling technique. SI values in lean former GDM women were similar to those in their controls (4.42 +/- 1.3 X 10(-4) ml min-1 microU-1 vs. 5.19 +/- 1.2 X 10(-4). In contrast, SI values in obese former GDM women were significantly lower than those in their controls (0.77 +/- 0.28 X 10(-4) vs. 2.04 +/- 0.43 X 10(-4). To assess whether differences in fat distribution and fat cell size were associated with these differences in insulin sensitivity, the waist to thigh circumference ratio, the waist to hip ratio, and abdominal fat cell diameter were measured. All three were significantly greater in the obese former GDM women than in controls. Thus, an abnormal central distribution of adiposity appears to be associated with the insulin action defect in obese former GDM women. We conclude that both lean and obese former GDM women have insulin secretion defects. Although a modest insulin action defect in lean former GDM women may have been missed by this technique, only in the obese former GDM women, who have a higher risk for future NIDDM, was an insulin action defect demonstrable. Thus, impairments of both insulin secretion and insulin action may be necessary to cause a marked predisposition toward NIDDM.
Asunto(s)
Tejido Adiposo/patología , Diabetes Mellitus/fisiopatología , Insulina/sangre , Islotes Pancreáticos/fisiopatología , Obesidad , Embarazo en Diabéticas/fisiopatología , Adulto , Antropometría , Complicaciones de la Diabetes , Diabetes Mellitus/patología , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/fisiología , Embarazo , Embarazo en Diabéticas/complicaciones , Embarazo en Diabéticas/patologíaRESUMEN
To analyze B-cell mechanisms in obesity, we measured the relationship (slope of potentiation) between glucose levels and acute insulin responses (AIR) to isoproterenol or arginine in nondiabetic subjects ranging from lean to markedly obese. Obese men (n = 9) had higher AIRs to isoproterenol than lean men (n = 11) at basal glucose levels [52 +/- 9 (SEM) vs. 32 +/- 5 microU/mL; P less than 0.05], and the difference increased as the ambient glucose level was raised (at 230 mg/dL; 263 +/- 22 vs. 140 +/- 21 microU/mL; P less than 0.0008). The individuals' slopes of glucose potentiation of AIR to isoproterenol were positively correlated with their excess weight (r = 0.72; P less than 0.001). Similar results were found when arginine was used as the secretagogue in other men and in women; the slope of potentiation was positively correlated with excess weight in both men and women (both P less than 0.005), although the effect of excess weight on slope was 51% greater among men (P less than 0.03). An independent measurement of insulin sensitivity (the Bergman SI) was made in the women. The potentiation slope was inversely correlated with SI (P less than 0.0001), indicating that the effect of obesity on insulin secretion is correlated with insulin resistance. These results characterize one mechanism contributing to the hyperinsulinemia of obesity and highlight the importance of considering the prevailing insulin sensitivity when assessing islet function.
Asunto(s)
Insulina/fisiología , Islotes Pancreáticos/fisiopatología , Obesidad/fisiopatología , Adulto , Arginina/farmacología , Glucemia/metabolismo , Femenino , Humanos , Insulina/sangre , Resistencia a la Insulina , Isoproterenol/farmacología , Masculino , Persona de Mediana EdadRESUMEN
To determine the effect of tolbutamide on glucagon release in noninsulin-dependent diabetic and normal subjects and how plasma glucose levels may modulate this effect, the acute glucagon response (AGR) to a 5-g iv arginine pulse was determined before and during a tolbutamide infusion. There was a decrease in plasma glucose concentration in both normal and diabetic subjects (both P less than 0.001); there tended to be a suppression of the AGR (4 of 6 normals and 8 of 11 diabetics), but this suppression was not statistically significant. In separate studies, when the plasma glucose level was clamped at baseline values by a variable rate of glucose infusion, the AGR was suppressed during the tolbutamide infusion in all 7 normal [change in AGR (delta AGR) = -35 +/- 12 pg/ml; P less than 0.05] and all 6 noninsulin-dependent diabetic subjects (delta AGR = -14 +/- 5 pg/ml, p less than .05). In 6 insulin-dependent diabetic subjects, there was no evidence of glucagon suppression by tolbutamide (delta AGR = +2 +/- 2 pg/ml). These results are consistent with the hypothesis that sulfonylureas suppress glucagon secretion by augmenting insulin secretion, an effect that falling glucose levels can mask. Consideration of this observation is necessary when interpreting the effects of a sulfonylurea on islet cell responses.