Glycaemic responses to different carbohydrate foods in healthy and diabetic blacks in Soweto.

Diabetes mellitus is uncommon in rural southern African blacks. With urbanisation and lifestyle changes, incidence rises to that in western populations. To assess associated changes in carbohydrate metabolism, glycaemic responses to glucose, refined maize, refined rice and bread were studied in 8 healthy and 8 non-insulin-dependent diabetic urban blacks. Additionally, in the healthy group serum insulin responses were measured. In the healthy, maize (the staple food of blacks) elicited the highest glucose response (207 mmol/l/min) and bread the lowest (107 mmol/l/min). The glycaemic indices of maize and glucose were similar. Serum insulin responses to maize were significantly lower than that of bread at 90 minutes (maize 66 muU/ml; bread 93 muU/ml; P = 0.02). In diabetics, maize and glucose elicited similar glycaemia (928 mmol/l/min and 921 mmol/l/min respectively). The high glucose response to maize could relate to its processing and physical form. The low insulin secretion could be due to inadequate stimulation by the 'entero-insular' axis. Moreover, variability in glucose insulin responses could stem from ethnic or genetic reasons. In the dietary management of black diabetics, refined maize should be replaced by other cereals.     

Hormonal and metabolic responses to an oral glucose load in obese Black diabetics.

Plasma insulin responses to a 4-hour glucose tolerance (100 g) were studied in urbanized Black people. Persons of normal weight without diabetes (12) and obese persons without diabetes (18) were compared with obese diabetics (19). Fasting serum ketone levels were measured, and the plasma potassium, triglyceride and growth hormone responses during the glucose tolerance test were determined. Obese subjects without diabetes had a twofold greater total plasma insulin response (area under curve) than their counterparts of normal weight, but there was a progressive fall in total plasma insulin response from subjects with mild diabetes (with fasting normoglycaemia) to those with severe diabetes (with fasting hyperglycaemia). The early plasma insulin responses of the group with mild diabetes were significantly impaired, and the peak response was only reached at 120 minutes. The subjects with severe diabetes had a flat insulin response curve. Fasting serum ketone levels were highest in the group with severe diabetes. The growth hormone responses were similar in all the groups. Plasma potassium and tryglyceride levels fell less during the glucose tolerance test in the group with severe diabetes than in the other three groups. These data indicate that insulin secretion is reduced in obese Blacks with chemical evidence of diabetes and this reduction becomes severe in the symptomatic diabetic.     

Effects of ingestion of triglyceride or galactose on secretion of gastric inhibitory polypeptide and on responses to intravenous glucose in normal and diabetic subjects

Responses of plasma immunoreactive gastric inhibitory polypeptide (IRGIP) to oral triglyceride or galactose were compared in normal and mildly diabetic (non-insulin-dependent) subjects. After triglyceride the responses of IRGIP were similar, but after galactose those of the diabetics were slightly exaggerated. Both stimuli evoked increments of plasma immunoreactive glucagon (IRG) in diabetics but not in normal subjects. Plasma immunoreactive insulin (IRI) did not change. In normal subjects given oral triglyceride or galactose followed by intravenous (I.V.) glucose the early-phase response of plasma IRI was enhanced and glucose tolerance improved. In the diabetics, oral triglyceride did not affect insulin release or glucose tolerance after I.V. glucose; oral galactose elicited a slight increase of insulin release without improving glucose tolerance. In the diabetics the rise of plasma IRG after ingestion of triglyceride or galactose was maintained after I.V. glucose. It is concluded that endogenous GIP is insulinotropic and that there is partial resistance to this action in diabetes. The results were compatible with feedback inhibition of GIP secretion by insulin and with the suggestion that the rise of plasma IRG associated with secretion of GIP in diabetics may be due to the glucagonotropic action of this peptide.     

Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations

Mutations in the high-affinity sulfonylurea receptor (SUR)-1 cause one of the severe recessively inherited diffuse forms of congenital hyperinsulinism or, when associated with loss of heterozygosity, focal adenomatosis. We hypothesized that SUR1 mutations would render the beta-cell insensitive to sulfonylureas and to glucose. Stimulated insulin responses were compared among eight patients with diffuse hyperinsulinism (two mutations), six carrier parents, and ten normal adults. In the patients with diffuse hyperinsulinism, the acute insulin response to intravenous tolbutamide was absent and did not overlap with the responses seen in either adult group. There was positive, albeit significantly blunted, acute insulin response to intravenous dextrose in the patients with diffuse hyperinsulinism. Graded infusions of glucose, to raise and then lower plasma glucose concentrations over 4 h, caused similar rises in blood glucose but lower peak insulin levels in the hyperinsulinemic patients. Loss of acute insulin response to tolbutamide can identify children with diffuse SUR1 defects. The greater response to glucose than to tolbutamide indicates that ATP-sensitive potassium (KATP) channel-independent pathways are involved in glucose-mediated insulin release in patients with diffuse SUR1 defects. The diminished glucose responsiveness suggests that SUR1 mutations and lack of KATP channel activity may contribute to the late development of diabetes in patients with hyperinsulinism independently of subtotal pancreatectomy.     

Endocrine-metabolic function in remission-phase IDDM during administration of cyclosporine

We have studied the endocrine-metabolic status of patients in non-insulin-receiving (NIR) remission of insulin-dependent diabetes mellitus (IDDM) within 6-60 mo of diagnosis during administration of cyclosporine, in comparison with nondiabetic subjects. IDDM patients in NIR remission were recognized when target glycemic control (plasma glucose and mean capillary blood glucose levels less than 7.8 mM before meals) was maintained without administration of insulin for at least 2 wk. In so-called isoglycemic tests, 50 g glucose was administered orally, and the glycemic curve was simulated in a subsequent study by programmed intravenous infusion of glucose. Under these conditions, the subjects with diabetes exhibited obvious glucose intolerance: acute beta-cell responses to intravenous glucose were virtually absent but significant, although subnormal responses were present after oral glucose. The responses of plasma immunoreactive gastric inhibitory polypeptide to oral glucose were normal. After bolus intravenous injections of glucose, the patients with diabetes again exhibited glucose intolerance; acute responses of immunoreactive insulin (IRI) and C-peptide were present, although grossly obtunded. On intravenous infusion of arginine (30 g in 30 min), the patients with diabetes showed substantial but subnormal increases in plasma IRI and C-peptide. Intravenous infusion of arginine elicited increments of plasma immunoreactive glucagon (IRGI) in both groups, and this response was slightly exaggerated in the patients with diabetes. On ingestion of a standard mixed meal (Sustacal) delivering 600 cal, there was a modest but significantly greater increase in plasma glucose levels in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Normalization of the paradoxic secretion of glucagon in diabetics who were controlled by the artificial beta cell.

Since it is important to elucidate the precise significance of pancreatic A-cell hypersecretion in the pathogenesis of diabetes mellitus, the change in the immunoreactive glucagon (IRG) response to 100 g oral glucose challenges was studied in diabetics whose blood glucose responses and plasma immunoreactive insulin concentrations (IRI) simulated those in normal subjects with the aid of the artificial beta cell system that we developed originally. In six nonobese adult-onset and four insulin-dependent diabetics whose blood glucose responses and plasma insulin concentrations after 100 g oral glucose load were made equivalent to those seen in normal subjects by the artificial beta cell, the glucagon release was similar to the response in normal subjects. In one insulin-dependent diabetic with high anti-insulin-binding capacity, the blood glucose response after an oral glucose challenge was not normalized by the artificial beta cell and the glucagon secretion was paradoxically increased. This fact suggested that the paradoxic rise in glucagon, seen in response to an oral glucose load in some diabetics, is secondary to insulin deficiency.     

Quantification of insulin secretion and in vivo insulin action in nonobese and moderately obese individuals with normal glucose tolerance

Insulin secretion and in vivo insulin action were quantified in nonobese and moderately obese subjects (approximately 35% above desirable body weight) with normal glucose tolerance. Insulin secretion was estimated by determining plasma insulin responses to a 75-g oral challenge, and in vivo insulin-stimulated glucose uptake by the euglycemic clamp technique. Plasma glucose levels of the two groups were identical during the glucose tolerance test, but the plasma insulin response was significantly greater (P less than 0.01) in the obese subjects. However, insulin-stimulated glucose utilization by the two groups was equal during the euglycemic clamp studies. These results were supported by the fact that degree of obesity correlated significantly with insulin response (r = 0.61, P less than 0.005), but not with insulin-stimulated glucose utilization (r = -0.25, P greater than 0.2). Thus, indirect evidence that moderately obese subjects were more insulin-resistant based on measurement of plasma insulin response was not supported by direct quantification of insulin action. One explanation for these findings is that the height of the plasma insulin response bears no relationship to loss of in vivo insulin action, but that seems unlikely in view of the fact that there was a significant correlation (r = -0.52, P less than 0.01) between these two variables in the group as a whole. Therefore, it appears that the hyperinsulinemia seen in obese individuals may not be a simple function of insulin resistance, and that ability of insulin to stimulate glucose utilization is not significantly impaired in moderately obese subjects with normal glucose tolerance. Alternatively, the degree of impairment in insulin action seen in these individuals is insufficient to be detected by the euglycemic clamp technique.     

Glucose-insulin interactions during cardiopulmonary bypass. Hypothermia versus normothermia

Since hypothermia is commonly used to lower local and general metabolism during cardiopulmonary bypass, we attempted to identify its specific effects on glucose-insulin interactions. A group of nondiabetic patients undergoing hypothermic (28 degrees C) cardiopulmonary bypass with ischemic (cold) cardiac arrest was compared to a similar group operated on under normothermic conditions with potassium cardioplegia. In the absence of exogenous dextrose administration, hypothermia blocked insulin secretion for the duration of the operation. It also inhibited insulin secretion in response to an exogenous dextrose load (e.g., the priming fluid of the cardiopulmonary bypass circuit) or a glucagon injection, but this inhibition was lifted by rewarming. Blood glucose levels, which during normothermia were mildly elevated even in the absence of dextrose administration, remained normal during the hypothermic phase of cardiopulmonary bypass. By the end of the rewarming period, however, blood glucose levels had reached the same level as observed under normothermic bypass, a fact suggesting that the cold inhibition of hepatic glucose production had been only temporary. Cold inhibition of hepatic glucose production also explains why glucose clearance after a sudden dextrose load was initially faster at low body temperature than at normal temperature. Glucose-clamp studies indicated that insulin resistance was initiated by anesthesia and surgical trauma, and further accentuated by cardiopulmonary bypass, in association with elevated levels of hormones indicative of surgical stress. Regardless of body temperature changes, the assimilation of glucose by nondiabetic subjects during and immediately after bypass called for the infusion of large doses of insulin. A comparison with diabetic subjects showed that insulin-dependent patients (type I diabetes) required no more insulin during cardiopulmonary bypass than normal subjects, whereas patients with type II diabetes exhibited a marked insulin resistance during the operation and in the immediate postoperative period.     

Important role of adrenergic mechanisms in acute glucose counterregulation following insulin-induced hypoglycemia in type I diabetes. Evidence for an effect mediated by beta-adrenoreceptors

During hypoglycemia induced by an i.v. insulin infusion for 60 min, rates of plasma glucose (PG) decrease and recovery, PG nadir, and plasma counter-regulatory hormone and free fatty acid responses were studied in eight type I uncomplicated diabetic subjects and eight nondiabetic subjects. Each subject was tested three times at two different rates of insulin infusion (25 and 32 mU/m2/min): (1) during infusion of saline, (2) during infusion of phentolamine + propranolol (combined alpha, beta-blockade), and (3) during infusion of propranolol alone (isolated beta-blockade) for 150 min. At the time of the studies, the diabetic subjects had been made euglycemic by an overnight i.v. insulin infusion. During infusion of insulin (25 mU/m2/min) and saline, the rates of PG decrease and recovery were slower (P less than 0.01) and PG nadir was delayed in the diabetic subjects. Moreover, their plasma glucagon response was blunted while plasma epinephrine, norepinephrine, growth hormone, and cortisol responses were similar in both groups. Infusion of insulin at 32 mU/m2/min caused larger decreases in PG than had been observed when insulin was infused at 25 mU/m2/min. Plasma glucagon responses increased in the nondiabetic subjects (P less than 0.05) but not in the diabetic subjects. However, in the diabetic subjects, plasma epinephrine increased more than in the nondiabetic subjects (P less than 0.05). There was an inverse correlation between the individual plasma epinephrine responses and the plasma glucagon responses in the diabetic subjects (r = -0.72) but not in the nondiabetic subjects. Alpha, beta-adrenergic blockade decreased the plasma glucose nadir and impaired the rate at which normoglycemia was restored in the diabetic subjects (P less than 0.005 vs. saline) but not in the nondiabetic subjects. Plasma catecholamine and growth hormone responses were increased and plasma FFA recovery was suppressed in both groups (P less than 0.05 vs. saline), while the cortisol responses were unaltered. During isolated beta-adrenergic blockade, changes in plasma glucose, counterregulatory hormones and FFA were essentially identical to those observed during combined alpha, beta-adrenergic blockade in both groups except that the augmented plasma norepinephrine responses were no longer apparent. Conclusions: although epinephrine is not essential for prompt restoration of normoglycemia in normal man following insulin-induced hypoglycemia, it plays a major role in glucose counterregulation in diabetics who have an impaired glucagon secretion in response to hypoglycemia. These counterregulatory effects of epinephrine are mediated by beta-adrenoreceptors.     

Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes

Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion (GSIS). This response is blunted in type 2 diabetes (T2DM). Xenin-25 is a 25-amino acid neurotensin-related peptide that amplifies GIP-mediated GSIS in hyperglycemic mice. This study determines if xenin-25 amplifies GIP-mediated GSIS in humans with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or T2DM. Each fasting subject received graded glucose infusions to progressively raise plasma glucose concentrations, along with vehicle alone, GIP, xenin-25, or GIP plus xenin-25. Plasma glucose, insulin, C-peptide, and glucagon levels and insulin secretion rates (ISRs) were determined. GIP amplified GSIS in all groups. Initially, this response was rapid, profound, transient, and essentially glucose independent. Thereafter, ISRs increased as a function of plasma glucose. Although magnitudes of insulin secretory responses to GIP were similar in all groups, ISRs were not restored to normal in subjects with IGT and T2DM. Xenin-25 alone had no effect on ISRs or plasma glucagon levels, but the combination of GIP plus xenin-25 transiently increased ISR and plasma glucagon levels in subjects with NGT and IGT but not T2DM. Since xenin-25 signaling to islets is mediated by a cholinergic relay, impaired islet responses in T2DM may reflect defective neuronal, rather than GIP, signaling.     

The disposal of intravenous glucose studied using glucose and insulin clamp techniques in sepsis and trauma in man

Whole body glucose uptake and oxidation during a hyperglycemic clamp have been shown to be depressed in hypermetabolic septic patients compared to control subjects despite similar plasma insulin concentrations. Forearm glucose uptake was similarly impaired. Metabolic rate was not increased further by the glucose infusion in the patients although a 20% rise was elicited in the controls. This resistance to the effects of insulin was also clearly demonstrated in trauma patients using the euglycemic clamp technique. The maximal rate of glucose disposal after injury was half that found in controls and the pattern of response was consistent with the insulin resistance being a post-receptor defect.     

Ethnic variability in the plasma insulin response to oral glucose in Polynesian and Micronesian subjects.

The pattern of insulin response to oral glucose over a wide range of glucose tolerance has been studied in two separate ethnic groups--Polynesians and Micronesians. Fasting insulin concentrations were relatively unchanged over the entire range of glucose tolerance in both populations, irrespective of whether comparable lean or obese samples of both groups were studied. The patterns of 2-h plasma insulins were similar over the whole range of glucose tolerance in Polynesians and Micronesians. However, in the comparisons of all subjects, or lean or obese groups of these populations, the plasma insulin concentrations of the Micronesians were both consistently and significantly higher. As the data analysis was arranged to take into account groups with identical 2-h plasma glucose concentrations and comparable degrees of obesity, the differences cannot be attributed to differences in the glucose levels or in obesity. In the presence of similar fasting insulin concentrations, these findings imply an ethnic variability in the pancreatic beta-cell response to oral glucose.     

Beta-endorphin modulation of the glucoregulatory effects of repeated epinephrine infusion in normal dogs

Successive epinephrine infusions were used as a partial model to examine hormonal and metabolic responses to repeated stress stimuli. As both the endogenous opiates and epinephrine are released in response to stress, we have also studied interactions between epinephrine and B-endorphin. Epinephrine (0.1 microgram/kg . min) was infused for 60 min, followed by a 60-min recovery, in nine normal, conscious dogs. In a similar study, B-endorphin (0.06 microgram/kg . min) was given 30 min before epinephrine, then continuously infused throughout the study (N = 4 dogs). When epinephrine was infused, levels rose to 600-800 pg/ml. The changes in glucagon, B-endorphin, FFA, and hepatic glucose production were similar during both epinephrine infusions, but there was a diminished insulin response, a greater decrease in glucose metabolic clearance, and a greater increase in plasma glucose with the second epinephrine infusion. When B-endorphin was given, plasma levels increased to 5.3 ng/ml. Compared with the infusion of epinephrine alone, there was a much greater rise in plasma glucose due to greater suppression of glucose metabolic clearance. With the second epinephrine infusion, however, the changes in glucose concentration were not substantially different from those seen during the second infusion of epinephrine alone, as both hepatic glucose production and glucose metabolic clearance were suppressed. B-endorphin diminished the insulin and glucagon responses during the first epinephrine infusion and abolished them during the second, but did not alter the FFA, ACTH, or cortisol responses to epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal glucose modulation of islet A- and B-cell responses to arginine in non-insulin-dependent diabetes mellitus

To assess the normality of islet A- and B-cell responses to a nonglucose secretogogue as well as the modulating effect of glucose in NIDDM, we examined plasma C-peptide and glucagon responses to arginine in eight patients with NIDDM and in six age- and weight-matched nondiabetic volunteers under conditions of identical hypoglycemia (approximately 70 mg/dl), euglycemia (94 mg/dl), and hyperglycemia (approximately 190 mg/dl). Plasma C-peptide responses to glucose and to arginine in the diabetic subjects were both significantly reduced at all glucose concentrations studied (P less than 0.01-0.005). The modulating effect of glucose on both islet A- and B-cell responses (slope of relation between plasma C-peptide or glucagon response versus plasma glucose concentration) was reduced greater than 80% in the diabetic subjects (P less than 0.01). We conclude that islet A- and B-cell responses to nonglucose secretogogues are abnormal in patients with NIDDM and that this may result from a functional defect in the modulating effect of glucose on insulin and glucagon secretion, which in some patients may be compensated for by hyperglycemia.     

Differential sensitivity to beta-cell secretagogues in "early," type I diabetes mellitus

The insulin secretory response to various beta-cell secretagogues was studied in four children (ages 11, 11, 12, and 10 yr) in "early" stages or remission of type I diabetes mellitus. One child was an anti-islet antibody positive monozygotic twin of a type I diabetic subject, two children had impaired glucose tolerance and elevated levels of Ia-positive T-cells, and the fourth was in remission (off insulin) of type I diabetes 6 mo after immunotherapy. The peak first-phase (0-10 min) insulin increment after intravenous (i.v.) glucose was negligible in each patient, whereas the peak responses to i.v. glucagon, tolbutamide, arginine, and oral glucose ranged between 10% and 43% of median responses in normal control subjects. The rank order of response to a variety of secretagogues was remarkably similar in all four subjects: i.v. arginine greater than i.v. glucagon greater than oral glucose greater than i.v. tolbutamide greater than i.v. glucose. These studies indicate that a "functional" beta-cell defect, namely a complete loss of response to i.v. glucose and a partial loss to other secretagogues, exists in type I diabetic patients before complete beta-cell destruction. This alteration in beta-cell responsiveness probably underlies our prior observation of slowly progressive loss of i.v.-glucose-induced insulin release in islet cell antibody-positive siblings to type I diabetic subjects.     

Epidural analgesia and postoperative lipid metabolism: stable isotope studies during a fasted/fed state

BACKGROUND AND OBJECTIVES: Although previous studies have reported an inhibitory effect of epidural block and glucose feeding on plasma concentrations of glycerol and free fatty acids (FFA), it remains unclear how epidural analgesia modifies the postoperative production and uptake of lipid metabolites. This can be achieved by determining the rate of lipolysis during a feeding state with dextrose. METHODS: Twelve patients with or without postoperative epidural analgesia were studied 48 hours after surgery. They underwent a 6-hour stable isotope infusion study using [1,1,2,3,3,-(2)H(5)] glycerol; 3 hours of fasting, and 3 hours of dextrose infusion (4 mg/kg/min). The rate of glycerol appearance (R(a) glycerol) i.e., rate of lipolysis, and plasma concentrations of glycerol, FFA, glucose, lactate, insulin, glucagon, and cortisol were measured during the fasted and the fed states. RESULTS: The rates of lipolysis were similar in both groups during the fasted state and were not modified by dextrose infusion. In contrast, plasma concentrations of glycerol and FFA were decreased significantly during the fed state (P <.01). Glycerol clearance (ratio between R(a) glycerol and plasma glycerol concentration) increased significantly in both groups (P <.05) with feeding. Similarly, plasma concentrations of glucose and insulin increased significantly following feeding with dextrose in both groups. CONCLUSIONS: The elevated rates of lipolysis associated with surgery cannot be suppressed by either epidural analgesia or dextrose feeding implying that the sustained stress response continues in the postoperative period and is the most important factor responsible for the increased release of glycerol.     

Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion

To evaluate the roles of counterregulatory hormones and insulin antibodies in the impairment of plasma glucose recovery from hypoglycemia in diabetes mellitus, and to assess the relationship between the glucagon response and duration of the disease, 21 insulin-dependent diabetic patients and 10 nondiabetic subjects were studied. The diabetics consisted of 5 patients with recent onset of diabetes (less than 1 mo); 11 with 2.6 +/- 0.3 (mean +/- SEM) yr duration of diabetes, 5 of whom had insulin antibodies; and 5 patients with long-term diabetes (21 +/- 3 yr), insulin antibodies, and autonomic neuropathy. During insulin-induced hypoglycemia (28 mU/m2 X min for 60 min) in patients with recent-onset diabetes, plasma free insulin, glucose, and counterregulatory hormone concentrations did not differ from those of nondiabetic subjects. In patients with insulin antibodies, the disappearance of insulin after insulin infusion was delayed, and both restitution of normoglycemia and plasma glucagon response were blunted compared with patients without antibodies. When glucagon was infused (80-130 ng/m2 X min) during hypoglycemia in diabetics with impaired glucagon responses in order to simulate normal glucagon responses, plasma glucose recovery was normalized in patients without antibodies but not in those with antibodies. In patients with long-standing diabetes, restitution of normoglycemia was further impaired and this was associated with an absent plasma glucagon response and a diminished plasma epinephrine response. Plasma glucagon responses to hypoglycemia were inversely correlated to the duration of diabetes (r = -0.943; P less than 0.0005). It is concluded that impaired A-cell secretion is the predominant mechanism for the delayed glucose recovery after hypoglycemia in diabetic patients without insulin antibodies and normal epinephrine responses. Slowed disappearance of insulin due to the presence of insulin antibodies further delays the restoration of normoglycemia. Patients with long-standing diabetes and autonomic neuropathy exhibit decreased epinephrine secretion, which leads to an additional retardation of glucose recovery. Since plasma glucagon and epinephrine responses to hypoglycemia were normal at the onset of diabetes but diminished in long-term diabetes, it appears that the impaired glucagon and epinephrine responses to hypoglycemia are acquired defects that develop subsequent to B-cell failure.     

Attenuated glucose recovery from hypoglycemia in the elderly.

Advanced age is a risk factor for hypoglycemia caused by sulfonylureas (and insulin) used to treat diabetes mellitus. Therefore, we hypothesized that there is an age-associated impairment of glucose counterregulation and further that this is the result of a sedentary life-style. To test these hypotheses, glycemic and neuroendocrine responses to hypoglycemia, produced by 0.05 U/kg body wt insulin i.v. were measured in nondiabetic elderly subjects (age 65.1 +/- 0.9 yr n = 23)--and in a subset (n = 11) again after 1 yr of physical training (which increased VO2 max by 5.2 +/- 0.9 ml.kg-1.min-1, P less than 0.05)--and compared with these responses in nondiabetic young subjects (23.8 +/- 0.6 yr, n = 18). Recovery from hypoglycemia was attenuated (analysis of variance P less than 0.001) in the elderly (plasma glucose recovery rate 29.4 +/- 2.2 vs. 42.7 +/- 5.0 microM/min, P less than 0.02). This attenuation was the result of a smaller counterregulatory increment in glucose production (maximum increment 13.3 +/- 1.1 vs. 17.2 +/- 1.1 mumol.kg-1.min-1; P less than 0.05) rather than a greater increment in glucose utilization in the elderly. The attenuated glucose recovery was associated with higher plasma insulin concentrations (maximum increment 1385 +/- 122 vs. 940 +/- 72 pM, P less than 0.01) and reduced glucagon responses to hypoglycemia (maximum increment 43 +/- 6 vs. 66 +/- 12 ng/L). The epinephrine, norepinephrine, cortisol, and growth hormone responses were similar, although the epinephrine response was slightly delayed and the growth hormone response appeared smaller in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-endorphin-induced inhibition and stimulation of insulin secretion in normal humans is glucose dependent

This study evaluated the effect of human beta-endorphin on pancreatic hormone levels and their responses to nutrient challenges in normal subjects. Infusion of 0.5 mg/h beta-endorphin caused a significant rise in plasma glucose concentrations preceded by a significant increase in peripheral glucagon levels. No changes occurred in the plasma concentrations of insulin and C-peptide. Acute insulin and C-peptide responses to intravenous pulses of different glucose amounts (0.33 g/kg and 5 g) and arginine (3 g) were significantly reduced by beta-endorphin infusion (P less than .01). This effect was associated with a significant reduction of the glucose disappearance rates, suggesting that the inhibition of insulin was of biological relevance. beta-Endorphin also inhibited glucose suppression of glucagon levels and augmented the glucagon response to arginine. To verify whether the modification of prestimulus glucose level could be important in these hormonal responses to beta-endorphin, basal plasma glucose concentrations were raised by a primed (0.5 g/kg) continuous (20 mg kg-1.min-1) glucose infusion. After stabilization of plasma glucose levels (350 +/- 34 mg/dl, t = 120 min), beta-endorphin infusion caused an immediate and marked increase in plasma insulin level (peak response 61 +/- 9 microU/ml, P less than .01), which remained elevated even after the discontinuation of opioid infusion. Moreover, the acute insulin response to a glucose pulse (0.33 g/kg i.v.) given during beta-endorphin infusion during hyperglycemia was significantly higher than the response obtained during euglycemia (171 +/- 32 vs. 41 +/- 7 microU/ml, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin resistance in diabetic ketoacidosis

The effect of "low-dose" (6--10 U/h) insulin treatment on the rate of decline of plasma glucose concentration was determined in 15 diabetic subjects admitted in ketoacidosis (plasma glucose = 948 79 mg/dl) and in six normal volunteers rendered hyperglycemic by a combined infusion of somatostatin and glucose (plasma glucose = 653 28 mg/dl). The fractional glucose turnover and the half-time of the fall in plasma glucose during insulin treatment were both 10-fold reduced (P less than 0.001) in the diabetics as compared with the controls. In the ketoacidotic subjects, the mean glucose clearance during insulin treatment was only 8% of that in the controls (P less than 0.001). In the normal subjects, tissue glucose clearance during insulin treatment of the hyperglycemia (5.8 0.7 ml/min . kg) was similar to that measured in the same subjects using a standard technique to quantitate insulin sensitivity (euglycemic insulin clamp). In the ketoacidotic patients, a history of prior insulin therapy, but not the degree of hyperglycemia at the time of admission, was associated with a more rapid rate of decline of plasma glucose in response to insulin treatment. We conclude that marked insulin resistance is present in virtually all diabetics in ketoacidosis.