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Biomedical subjects

R Rizza

Publications and source records attributed to R Rizza.

At least 37 records · Page 2Linked to original sources
PubMed1989

Comparison of the pattern of postprandial carbohydrate metabolism after ingestion of a glucose drink or a mixed meal.

To determine whether the postprandial pattern of carbohydrate metabolism differs after ingestion of an identical amount of glucose as either a drink or as a part of a mixed meal, normal subjects were studied on two occasions. On both occasions, hepatic and extrahepatic glucose metabolism were assessed using the dual isotope and forearm catheterization techniques as well as indirect calorimetry. Plasma glucose, insulin, and C-peptide concentrations and rate of systemic entry of ingested glucose all were lower (P less than 0.05) during the first 15 min after the mixed meal than after the glucose drink. The integrated C-peptide response was greater (P less than 0.05) after the mixed meal, whereas the integrated suppression of glucagon was greater (P less than 0.05) after the glucose drink. Despite these differences in circulating hormone concentrations, after the first 15 min, the rates of systemic entry of ingested glucose, endogenous glucose release, incorporation of carbon dioxide into glucose, and glucose and lipid oxidation as well as nonoxidative glucose storage were virtually the same after the mixed meal and the glucose drink. We conclude that the pattern of postprandial carbohydrate metabolism after ingestion of a glucose meal is remarkably similar to that after ingestion of a more traditional mixed meal. These data suggest that insights regarding the pattern of postprandial carbohydrate metabolism derived from previous studies employing only a glucose drink are likely to pertain to those observed when healthy individuals ingest a meal that contains protein and fat.

Adult↗
PubMed1988

Insulin action in insulin-dependent diabetes mellitus (type I): measurement during constant and changing insulin concentrations.

To test the hypothesis that insulin resistance in type I diabetes mellitus is characterized by a decrease in the rate as well as the amplitude of response to insulin, seven patients with diabetes mellitus and 12 subjects without diabetes were given an identical amount of insulin on two occasions: once as a primed constant and once as a variable eight-step infusion. On both occasions plasma glucose concentrations were maintained in the euglycemic range by means of an exogenous glucose infusion. The amplitude of stimulation of glucose utilization was decreased (p less than 0.05) in the type I patients compared with the subjects without diabetes during both a constant and a variable insulin infusion, whether measured as the peak (2.24 +/- 0.11 mg/kg/min vs 3.18; +/- 0.18 mg/kg/min constant and 2.80 +/- 0.30 mg/kg/min vs 3.54 +/- 0.23 mg/kg/min variable) or integrated response above basal (54 +/- 2 mg/kg vs 115 +/- 26 mg/kg constant and 60 +/- 26 mg/kg vs 147 +/- 21 mg/kg, variable). In addition, the rate of activation of glucose utilization (slope 0 to 90 minutes) was decreased (p less than 0.02) in the type I patients compared with subjects without diabetes during both the constant (0.003 +/- 0.001 mg/kg/min 2 vs 0.008 +/- 0.002 mg/kg/min 2) and variable (0.006 +/- 0.002 mg/kg/min 2 vs 0.015 +/- 0.002 mg/kg/min 2) insulin infusions. Insulin antibody binding did not correlate with the severity of insulin resistance. We conclude that insulin resistance in patients with insulin-dependent diabetes mellitus is attributable to a decrease in both the rate and amplitude of response to insulin.

Adult↗
PubMed1987

Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity.

To determine the contribution of obesity to the insulin resistance of non-insulin-dependent diabetes mellitus, insulin dose response curves for suppression of glucose production and stimulation of glucose utilization were generated in lean and obese diabetic patients and compared to those observed in weight-matched nondiabetic subjects. Glucose utilization during 0.4, 1.0, and 10.0 mU/kg x min insulin infusions (producing insulin concentrations ranging from approximately 50 to 2,000 microU/mL) was lower (p less than .02 to .001) in lean and obese diabetic patients compared to weight-matched nondiabetic subjects indicating insulin resistance. Glucose utilization was not correlated with obesity in the diabetic subjects. Suppression of glucose production was impaired (P less than .03 and .001) in both the lean and obese diabetic subjects at physiologic but not supraphysiologic insulin concentrations. We conclude that patients with NIDDM have both hepatic and extrahepatic insulin resistance, the severity of which appears to be independent of the degree of obesity.

Blood Glucose↗
PubMed1987

Use of a variable insulin infusion to assess insulin action in obesity: defects in both the kinetics and amplitude of response.

To determine whether the severity of insulin resistance in obesity, as assessed by the traditional hyperinsulinemic glucose clamp, reflects the severity of resistance present during changing insulin concentrations, such as occur after meal ingestion, 9 moderately obese and 12 lean subjects were studied on 2 occasions: once during a primed continuous insulin infusion and once during a variable 8-step insulin infusion. Identical amounts of insulin were given on each occasion, and euglycemia was maintained by a glucose infusion. Stimulation of isotopically determined glucose utilization above the basal value was lower in the obese than in the lean subjects during the variable [2.4 +/- 0.5 (+/- SEM) vs. 5.4 +/- 0.7 g/m2; P = 0.004] and the constant (2.9 +/- 0.7 vs 4.2 +/- 0.9 g/m2; P = 0.32) insulin infusions; however, the differences were only significant with the variable insulin infusion. The variable insulin infusion also was associated with lower rates of activation of glucose utilization (slope, 0-90 min, 0.27 +/- 0.05 vs. 0.55 +/- 0.09 mg/m2 X min 2; P = 0.01) in obese compared to lean subjects. In contrast, rates of activation during the low constant infusion (0.24 +/- 0.05 vs. 0.29 +/- 0.06 mg/m2 X min 2; P = 0.51) did not differ in the lean and obese subjects. Despite identical amounts of insulin, stimulation of glucose utilization was greater (P less than 0.03) during the variable than during the constant insulin infusion in the lean subjects. In contrast, stimulation during the variable and constant insulin infusions was equal in the obese subjects. These observations indicate that insulin resistance in obesity is due to a defect in the rate as well as absolute response achieved and suggest that under conditions of daily living the contribution of insulin resistance to impaired carbohydrate tolerance is greater than that previously estimated by a constant insulin infusion.

Adult↗
PubMed1986

Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy.

Pathological, morphometric, and teased fiber studies of sural nerve from 36 diabetic patients with (n = 32) and without (n = 4) neuropathy and from 47 healthy subjects provide evidence that in diabetic polyneuropathy: (1) fiber loss is primary; (2) demyelination and remyelination with or without onion bulb formation are secondary; (3) remaining fibers, on average, have the same ratio of small to large fibers as in healthy individuals, but with a greatly increased variability; and (4) the spatial distribution of fiber loss is both diffuse and multifocal. Criteria developed during the study of experimental models of ischemic neuropathy were employed to assess whether ischemic nerve damage had occurred in diabetic polyneuropathy. We conclude that there is increasing evidence that microvascular pathological abnormality and ischemia may be involved in the pathogenesis of human diabetic polyneuropathy. Cases with selective loss of small or large afferent fibers are probably extremes of a normal distribution and not different disorders.

Adult↗
PubMed1986

Insulin resistance in acromegaly: defects in both hepatic and extrahepatic insulin action.

Short-term growth hormone excess is associated with impaired hepatic and extrahepatic responses to insulin in the absence of a change in insulin binding. To determine whether similar defects occur after chronic growth hormone excess, insulin dose-response curves for stimulation of glucose utilization and suppression of glucose production and monocyte and erythrocyte insulin binding were determined in five acromegalic patients and six healthy volunteers of comparable age, sex, and obesity. During infusion of insulin, glucose infusion rates required to maintain euglycemia were significantly lower (P less than 0.02 all) in the acromegalic patients than in the control subjects. Suppression of glucose production was impaired in the acromegalic subjects at insulin concentrations in the physiological range but not at insulin concentrations in the supraphysiological range. In contrast stimulation of glucose utilization was decreased in the acromegalic subjects at both physiological and supraphysiological insulin concentrations. Neither monocyte nor erythrocyte insulin binding differed significantly in the acromegalic and control subjects. These data indicate that chronic growth hormone excess is associated with a defect in both hepatic and extrahepatic insulin action. The decrease in glucose utilization at supraphysiological insulin concentrations in the acromegalic subjects and the normal monocyte and erythrocyte insulin binding suggest a postbinding alteration in insulin action.

Acromegaly↗
PubMed1986

The role of autoregulation of the hepatic glucose production in man. Response to a physiologic decrement in plasma glucose.

In man, a decrease in plasma glucose concentration results in a compensatory increase in hepatic glucose release. Studies in vitro have suggested that a low glucose concentration per se may directly stimulate hepatic glucose release, an effect often referred to as autoregulation. Whether autoregulation occurs in man in response to a physiologic decrement in blood glucose is not known. Therefore, seven healthy, nonobese subjects were studied on two occasions to determine the role of autoregulation in mediating the increase in glucose production that accompanies a physiologic decrement in plasma glucose concentration. On both occasions, plasma glucose concentrations were clamped successively at 95, 65, and 95 mg/dl for 2 h each. Insulin (approximately 14 microU/ml) and glucagon (approximately 70 pg/ml) were maintained constant on both occasions by an infusion of somatostatin and insulin. Phentolamine and propranolol also were infused on one occasion to produce combined alpha- and beta-adrenergic blockade. In the absence of adrenergic blockade, glucose production increased by approximately 1.3 mg/kg X min when the plasma glucose concentration was decreased from 95 to 65 mg/dl and decreased by approximately 1.5 mg/kg X min when glucose was increased from 65 to 95 mg/dl. In the presence of adrenergic blockade, the increase and decrease in glucose production averaged 0 and 0.5 mg/kg X min, respectively, representing 70-100% inhibition. We conclude that, in the presence of low physiologic insulin concentrations, autoregulation is not a major contributor to the hepatic response to a physiologic decrement in plasma glucose concentration in man.

Adult↗
PubMed1985

Diabetic neuropathy.

The incidence and prevalence of diabetic neuropathies in Insulin Dependent (IDDM) and Non-Insulin Dependent (NIDDM) Diabetes Mellitus is not known because in previous studies the heterogeneity of diabetes and of the neuropathies was not taken into account, criteria for diagnosis and surveillance for neuropathy were variable, and studies were not prospective or population based. We have begun such prospective epidemiologic studies using a uniform algorithm for the classification of the diabetic disorders and uniform and validated approaches for the assessment of symptoms, neurologic deficits and various quantitative end-points of neural dysfunction. As regards cause, a key question which we are trying to answer is whether hyperglycemia and associated metabolic alterations affect neural tissue directly or whether there is an intervening tissue alteration between metabolic derangement and tissue change. Improved control of hyperglycemia does not appear to be associated with rapid neurologic improvement, possibly arguing for an intervening tissue alteration. The recently observed decrease in nerve oxygen tension and blood flow in streptozotocin diabetes suggests that an alteration of the nerve microenvironment may relate importantly to the cause of diabetic neuropathy.

Diabetes Mellitus, Type 1↗
PubMed1985

Effect of thyroid hormone excess on action, secretion, and metabolism of insulin in humans.

To determine the effect of thyroid hormone excess on insulin secretion, metabolism and action in humans, we examined intravenous glucose tolerance, glucose-induced insulin secretion, insulin clearance, monocyte insulin receptor binding, and the dose-response characteristics for the effects of insulin on glucose production, uptake, oxidation, and nonoxidative disposal in 10 normal volunteers for 14 days before and after oral administration of triiodothyronine (T3) in doses that increased plasma T3 to levels observed in spontaneous thyrotoxicosis (P less than 0.001). After T3 postabsorptive plasma glucose (P less than 0.05) and insulin (P less than 0.05) both increased; intravenous glucose tolerance was unaffected, but plasma insulin responses were increased (P less than 0.01); basal glucose production, uptake, and oxidation all increased (all P less than 0.05), whereas nonoxidative glucose disposal was unaffected (P = NS); monocyte insulin receptor binding increased (P less than 0.01) due to increased receptor affinity (P less than 0.05); and receptor number was not significantly altered (P = NS). Insulin clearance was increased. Insulin-induced suppression of glucose production was impaired (Km 22 +/- 3 vs. 37 +/- 7 microU/ml, P less than 0.02); maximal insulin-induced glucose uptake (10.7 +/- 0.6 vs. 13.0 +/- 0.9 mg X kg-1 X min-1, P less than 0.001) and oxidation (3.41 +/- 0.30 vs. 5.34 +/- 0.59 mg X kg-1 X min-1, P less than 0.001) were increased without a significant change in Km. However, submaximal rates of nonoxidative glucose disposal and glucose uptake were inappropriately low for the increased insulin receptor binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Infusion of insulin impairs human adipocyte glucose metabolism in vitro without decreasing adipocyte insulin receptor binding.

To determine whether hyperinsulinaemia can cause insulin resistance in man and, if so, whether this occurs at a receptor or post-receptor site, nine normal volunteers were infused with insulin for 6 h at a rate (2 mU X kg-1 X min-1) which resulted in steady-state plasma insulin concentrations of 140 +/- 13 mU/l and four subjects were infused with saline (0.45%). Isolated adipocytes and monocytes were used as models for studying insulin binding, while adipocytes were also used to study insulin action in vitro. Adipocyte insulin binding did not decrease following infusion of insulin (4.6 +/- 0.5 versus 4.4 +/- 0.4% per 2 X 10(5) cells, before and after, respectively), whereas monocyte insulin binding did (7.2 +/- 0.6 versus 6.2 +/- 0.6% per 10(7) cells, p less than 0.05). Initial rates of adipocyte 3-0-methyl glucose transport were decreased in the absence of insulin (basal) and at submaximally effective (33.3 pmol/l) but not at maximally effective insulin concentrations. At all insulin concentrations and in the absence of insulin, rates of glucose conversion to lipids were decreased more than 50% (p less than 0.05), whereas rates of glucose oxidation were unaffected. This decrease in the rates of conversion of glucose to lipids could not be accounted for by the decrease in rates of glucose transport. These results suggest that hyperinsulinaemia can cause insulin resistance in man and that, at least initially, this occurs at a post-receptor site. Furthermore, the discordant effect of hyperinsulinaemia on monocyte and adipocyte insulin binding indicates that monocyte insulin binding may not always reflect insulin binding in insulin-sensitive tissues.

3-O-Methylglucose↗
PubMed1984

Comparison of porcine and semisynthetic human insulins using euglycemic clamp-derived glucose-insulin dose-response curves in insulin-dependent diabetes.

In order to compare the biologic effectiveness of porcine and semisynthetic human insulins, a euglycemic clamp method was used in eight insulin-dependent diabetic subjects. Each subject was tested for each insulin on separate days. In order to derive glucose-insulin dose-response curves for both insulins, sequential but constant infusion rates of 0.2, 0.5, 1.0, and 2.0 mU/kg/min were performed. Plasma glucose levels attained during the euglycemic clamp were 96 +/- 3 mg/dL. At each insulin infusion rate, the steady-state glucose infusion rate required to maintain euglycemia was measured. At each increment of insulin infused, steady-state glucose infusion rates for porcine insulin were 1.12 +/- 0.22, 1.90 +/- 0.59, 4.28 +/- 0.61, and 9.37 +/- 0.66 mg/kg/min compared with 1.27 +/- 0.42, 2.38 +/- 0.20, 4.25 +/- 0.43, and 8.87 +/- 0.67 mg/kg/min for semisynthetic human insulin. By ANOVA, no significant difference was noted between the two insulins. Because insulin infusion rates may not result in predictable circulating free insulin levels in subjects who have circulating insulin antibodies, free insulin levels were determined. When steady-state glucose infusion rates were compared with free insulin levels achieved at the four insulin infusion rates, dose-response curves for both porcine and semisynthetic human insulins were virtually identical. These data suggest that semisynthetic human insulin has equivalent biologic effects on overall glucose metabolism compared with porcine insulin in insulin-dependent diabetes.

Adult↗
PubMed1984

Influence of changes in insulin receptor binding during insulin infusions on the shape of the insulin dose-response curve for glucose disposal in man.

To determine the influence of insulin infusions used in dose-response studies on monocyte insulin binding, monocyte insulin binding and glucose disposal were measured in six normal subjects before and at the end of each of four sequential 2-h insulin infusions (0.4, 1.0, 2.0, and 10 mU kg-1 min-1). Monocyte insulin binding was unaltered at the end of the first three infusions (plasma insulin, 31 +/- 2 (SEM), 77 +/- 3, and 184 +/- 10 microU/ml) but was decreased after the last infusion (plasma insulin, 1730 +/- 125 microU/ml) at 0.2 through 10.2 ng/ml insulin concentrations in the binding assay (P less than 0.01). Using a one-site model, this could be ascribed to a decrease in insulin receptor affinity (1.54 +/- 0.26 vs. 2.27 +/- 0.48 X 10(8) M-1, P less than 0.05), whereas in a two-site model this appeared to be due to a decrease in high affinity binding sites (1,868 +/- 228 vs. 2,387 +/- 207, P less than 0.02). Nevertheless, insulin receptor occupancies estimated to occur during the insulin infusions were virtually identical whether preinsulin infusion binding data (745 +/- 72, 1,383 +/- 117, 2,572 +/- 302, and 10,092 +/- 1,708) or binding data at the end of each infusion (702 +/- 56, 1,367 +/- 150, 2,383 +/- 318, and 9,158 +/- 2,023) were used to calculate occupancy. These results indicate that although monocyte insulin binding decreased during dose-response experiments using sequential infusions of insulin, due to the concentrations of insulin at which this occurs this decrease did not alter the shape of the dose-response curve relating glucose disposal to monocyte insulin receptor occupancy.

Adolescent↗
PubMed1984

Mechanism of hyperglycemia and response to treatment with an inhibitor of fatty acid oxidation in a patient with insulin resistance due to antiinsulin receptor antibodies.

Severe hyperglycemia and insulin resistance due to antiinsulin receptor antibodies developed over a period of 3 months in a 50-yr-old insulin-requiring diabetic patient. The hyperglycemia resulted from overproduction of glucose due to excessive rates of glycogenolysis and gluconeogenesis rather than decreased glucose utilization. Treatment with methyl-2-tetradecylglycidate, an inhibitor of fatty acid oxidation, resulted in a decrease in plasma glucose concentration. This was associated with a decrease in the rate of glucose production due to decreases in both gluconeogenesis and glycogenolysis rates, as well as an increase in the respiratory quotient. Plasma glucose concentrations continued to respond to the drug for the next 2 months until the sudden development of terminal hypoglycemia. The hypoglycemic action of the drug is consistent with the existence of an insulin-independent effect of fatty acid oxidation on glucose metabolism in man.

Adipose Tissue↗
PubMed1982

Insulin increases the maximum velocity for glucose uptake without altering the Michaelis constant in man. Evidence that insulin increases glucose uptake merely by providing additional transport sites.

The present studies were undertaken to assess the mechanism by which insulin increases glucose uptake in man. Because glucose uptake in most mammalian tissues occurs predominantly by a facilitated transport system that follows Michaelis-Menten kinetics, glucose uptake was measured isotopically in normal volunteers over the physiologic range of plasma glucose and insulin concentrations and was subjected to Lineweaver-Burk and Eadie-Hofstee analysis. With both methods, increases in plasma insulin from 18 microunits/ml to 80 and 150 microunits/ml were found to increase the maximum velocity (Vmax) for glucose uptake nearly three- and fivefold, respectively, (P less than 0.025 and P less than 0.001) without significantly altering the Michaelis constant (Km). Because an increase in the affinity or molecular activity of transport sites or provision of additional transport sites that differed from those present basally should have altered the Km, whereas a mere increase in the number of transport sites would have only increased the Vmax, our results indicate that in man, insulin may increase glucose uptake merely by providing additional transport sites.

Adult↗
PubMed1982

Stimulation of human pancreatic polypeptide secretion by hypoglycemia is independent of adrenergic mechanisms.

Human pancreatic polypeptide (HPP) increases after insulin-induced hypoglycemia. To determine whether adrenergic mechanisms contribute to this increase in normal man, six subjects were studied on two occasions: once after insulin alone and once after insulin plus simultaneous alpha (phentolamine)- and beta (propranolol)-adrenergic blockade. Despite comparable hypoglycemia (51 +/- 4 vs. 49 +/- 4 mg/dl), the increase in HPP did not differ in the presence or absence of adrenergic blockade (721 +/- 215 vs. 736 +/- 193 pg/ml, respectively). These findings suggest that HPP secretion during hypoglycemia is not dependent on adrenergic mechanisms.

Adult↗
PubMed1981

Effect of intermittent physiologic hyperglucagonemia on postprandial plasma glucose levels in normal man.

The ability of glucagon to impair glucose tolerance has been questioned by studies involving infusion of exogenous glucagon during a glucose load. Since such hormone administration may not reflect the physiologic pattern of glucagon secretion and may result in hepatic downregulation to glucagon, the present experiments have examined the effects of intermittent endogenous hyperglucagonemia (induced by episodic infusion or arginine) on plasma glucose profiles of normal man following ingestion of mixed meals. In control studies following meal ingestion, plasma glucose, insulin and glucagon increased respectively 15-30 mg/dl, 30-60 uU/ml and 25-50 pg/ml. When meals were accompanied by arginine infusions, plasma glucagon responses were augmented three to fourfold (p less than 0.05). Amplitudes of glycemic excursions during infusion of arginine (345 +/- 40 mg/dl) were significantly augmented compared to those observed in control studies (286 +/- 34 mg/dl, p less than 0.02). These results indicate that intermittent increases in plasma glucagon within the physiologic range can adversely affect postprandial glucose profiles in normal man despite concomitant hyperinsulinemia and suggest that such hyperglucagonemia may contribute to impaired postprandial glucose tolerance in diabetic individuals in whom insulin secretion is deficient.

Adolescent↗