Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans

In the fasted rat, efficient glucose-stimulated insulin secretion (GSIS) is absolutely dependent on an elevated level of circulating free fatty acids (FFAs). To determine if this is also true in humans, nonobese volunteers were fasted for 24 h (n = 5) or 48 h (n = 5), after which they received an infusion of either saline or nicotinic acid (NA) to deplete their plasma FFA pool, followed by an intravenous bolus of glucose. NA treatment resulted in a fall in basal insulin concentrations of 35 and 45% and in the area under the insulin response curve (area under the curve [AUC]) to glucose of 47 and 42% in the 24- and 48-h fasted individuals, respectively. The 48-h fasted subjects underwent the same procedure with the addition of a coinfusion of Intralipid plus heparin (together with NA) to maintain a high concentration of plasma FFAs throughout the study. The basal level and AUC for insulin were now completely normalized (C-peptide profiles paralleled those for insulin). To assess the effect of an overnight fast, nonobese (n = 6) and obese (n = 6) subjects received an infusion of either saline or NA, followed by a hyperglycemic clamp (200 mg/dl). The insulin AUC in response to glucose was unaffected by lowering of the FFA level in nonobese subjects, but fell by 29% in the obese group. The data clearly demonstrate that in humans, the rise in circulating FFA levels after 24 and 48 h of food deprivation is critically important for pancreatic beta-cell function both basally and during subsequent glucose loading. They also suggest that the enhancement of GSIS by FFAs in obese individuals is more prominent than that seen in their nonobese counterparts.     

Mechanism of glucose intolerance during fasting: differences between lean and obese subjects

Oral glucose tolerance tests were performed on 14 lean and 14 obese nondiabetic subjects before and after a 6-day fast. In addition, insulin tolerance tests were performed on 8 lean and 8 obese subjects before and after starvation. Both in lean and obese subjects glucose tolerance deteriorated during starvation, but much more so in the lean population. During fasting, insulin elevation after a glucose load was significantly delayed in lean subjects but not in the obese. Circulating levels of factors known to affect glucose tolerance, such as glucagon, growth hormone, free fatty acids, and ketone bodies were higher in fasting lean than in fasting obese individuals. In normals fasting resulted in a significant decrease of the blood glucose response to insulin injection, whereas in fasting obese subjects glucose response was unchanged. The results obtained suggest that the effect of fasting on insulin release and insulin sensitivity was more pronounced in lean than in obese subjects, which resulted in greater deterioration of glucose tolerance in the lean population.     

Abnormal characteristics in young offspring of parents with non-insulin-dependent diabetes mellitus. The Bogalusa Heart Study

Non-insulin-dependent (type II) diabetes has a strong familial component. In 1989-1991, a community-based study of young Caucasian offspring (mean age, 15.3 years) of non-insulin-dependent (type II) diabetics (n = 25) and nondiabetics (n = 27) representing 13 and 12 families, respectively, was conducted in Bogalusa, Louisiana, to determine whether metabolic abnormalities could be detected in early life. All offspring were given a 1-hour oral glucose tolerance test. The offspring of diabetics (versus nondiabetics) had significantly increased measures of body fatness; blood pressure; and fasting levels of glucose, insulin, glucagon, insulin-to C-peptide ratio, and triglycerides. The increases of systolic blood pressure, glucose, and glucagon remained significant after adjustment for differences in body mass index (BM). After glucose challenge, only plasma glucose response was significantly higher in the offspring of diabetics, even after controlling for differences in BMI. None of the offspring of nondiabetics had 30-minute (peak) glucose levels above 161 mg/dl (8.9 mmol/liter), compared with 41% of the offspring from diabetics. High glucose response and BMI were independently associated with parental diabetes. These results indicate that it is possible to identify multiple abnormalities in some offspring of type II diabetics at an early age that may presage the onset of overt adult diabetes.     

Effects of oral glucose administration on plasma growth hormone levels in women with polycystic ovary syndrome

OBJECTIVE: To evaluate the sensitivity of GH secretion to the suppressive effect of oral glucose administration in women with polycystic ovary syndrome (PCOS). DESIGN: Comparison of the GH response to an oral glucose load in women with PCOS and in weight-matched normally menstruating women (controls). SETTING: Reproductive endocrinology unit. PATIENT(S): Eighteen obese and 11 nonobese patients and 10 obese and 10 nonobese controls. INTERVENTION(S): After an overnight fast, each woman underwent a 75-g, 3-hour oral glucose tolerance test (OGTT). MEAN OUTCOME MEASURE(S): Growth hormone, glucose, and insulin responses to OGTT. RESULT(S): No significant differences in the glycemic and insulinemic responses were found between the patients and the weight-matched controls. No decrease in plasma GH was observed in both obese and nonobese patients and in obese controls during the OGTT, whereas a significant GH decrease occurred in nonobese controls 60 and 120 minutes after glucose intake. CONCLUSION(S): Oral glucose administration was unable to suppress GH levels in nonobese as well as in obese women with PCOS and in obese control women. These data suggest that both PCOS and obesity are associated with a reduced sensitivity of GH secretion to glucose suppression.     

Effect of exercise intensity on glucose and insulin metabolism in obese individuals and obese NIDDM patients

OBJECTIVE: The primary purpose of this study was to evaluate the acute effect of exercise of differing intensity on plasma glucose and insulin responses to an oral glucose challenge. RESEARCH DESIGN AND METHODS: Six obese men and six obese men with NIDDM of similar age, weight, percentage body fat, and VO2peak participated in the study. Each subject underwent two 7-day exercise programs in a counterbalanced order at 2-week intervals. During each 7-day exercise period, the subjects cycled every day at a power output corresponding to 50% VO2peak for 70 min or 70% VO2peak for 50 min. Muscle glycogen utilization was estimated during exercise on day 7 using a [3H]glucose infusion technique in conjunction with indirect calorimetry. During the day before and after each 7-day exercise period, a 3-h oral glucose tolerance test (OGTT) was administered after a 12-h overnight fast. RESULTS: The average caloric expenditure did not differ between exercise at 50 and 70% VO2peak in both obese and obese NIDDM subjects. However, the carbohydrate oxidation was higher (P < 0.05) during exercise at 70 than 50% VO2peak in obese subjects (77 +/- 5 vs. 68 +/- 6 g) and obese NIDDM subjects (70 +/- 4 vs. 58 +/- 6 g). Muscle glycogen utilization was also higher (P < 0.05) during exercise at 70 than 50% VO2peak in obese subjects (59 +/- 9 vs. 30 +/- 7 g) and in obese NIDDM subjects (48 +/- 5 vs. 24 +/- 5 g). In obese subjects, plasma glucose response area during the OGTT did not change after 7 days of exercise at either 50 or 70% VO2peak. Plasma insulin response area during the OGTT also did not change after 7 days of exercise at 50% VO2peak. However, plasma insulin response area was reduced (P < 0.05) after 7 days of exercise at 70% VO2peak (9,644 +/- 1,783 vs 7,538 +/- 1,522 microU.ml-1.180 min-1). In obese NIDDM subjects, both plasma glucose and insulin response areas during the OGTT did not decrease after 7 days of exercise at either 50 or 70% VO2peak. CONCLUSIONS: It is concluded that the exercise-induced improvement in insulin sensitivity is influenced by exercise intensity in obese individuals. The improved insulin sensitivity after 7 days of exercise at 70% VO2peak in obese individuals may be related to greater muscle glycogen utilization during exercise. The lack of improvement in glucose tolerance and insulin sensitivity after 7 days of exercise at either 50 or 70% VO2peak in obese NIDDM patients may be due to the fact that the NIDDM patients selected in the present study were relatively hypoinsulinemic.     

Relationship between obesity and risk factors of coronary heart disease in nondiabetics

We analysed the data of 395 nondiabetic obese (BMI 25-42.2, impaired glucose tolerance, IGT, 257 and normal glucose tolerance, NGT, 138) and 482 nonobese subjects (BMI 15.9-24.9, IGT 170 and NGT 312). The blood pressure, plasma glucose, insulin, triglyceride and total cholesterol in obese were higher than that in nonobese, while HDL-c level was lower after controlling for age and sex (P < 0.001). This difference remained to be significant even after the adjustment of age, sex, insulin and 2-hours plasma glucose. Therefore, it was suggested that obesity was easy of access to coronary heart disease risk factors independent of hyperglycemia and hyperinsulinemia.     

Three dimensional stress analysis of the human femur

Plasma glucose, insulin and triglyceride changes in response to a standard breakfast and an oral glucose tolerance test have been studied in normal, obese and diabetic subjects. Mild diabetics with an abnormal oral glucose tolerance test may have normal or near-normal incremental glucose responses to a standard breakfast. A raised fasting plasma glucose is the predominant day-to-day glucose abnormality of mild diabetes. Diabetics have decreased insulin responses to oral glucose compared with the meal, and the deficient insulin response to glucose probably accounts for both the raised fasting plasma glucose levels and the abnormal oral GTT. The initial insulin response to a meal is normal in mild diabetics, and is probably stimulated by secretogogues other than glucose. The oral glucose tolerance test is apposite for the diagnosis of diabetes in view of the impaired insulin response to glucose, but accurate measurement of the basal plasma glucose may be of equal value. The diabetic and obese subjects had normal triglyceride levels, and there was no detectable impairment of disposal of the exogenous triglyceride following the breakfast.     

Characteristics of young offspring of type 2 diabetic parents in a biracial (black-white) community-based sample: the Bogalusa Heart Study

The impact of race (black-white) and family history of type 2 diabetes mellitus on metabolic characteristics in early life was examined in a community-based sample from Bogalusa, LA. Study subjects included offspring of type 2 diabetics (n = 53, 47% black) and nondiabetics (n = 52, 40% black), with the mean age of each group ranging from 14.2 to 15.6 years. Offspring were given a 1-hour oral glucose tolerance test. Measures of body fatness such as body weight, body-mass index (BMI; weight/height2), and triceps and subscapular thicknesses were significantly higher only in white offspring of diabetics versus nondiabetics; measures of abdominal fat (waist circumference and waist-to-hip ratio) were significantly higher among offspring of diabetics of both races. Among the measures of glucose homeostasis, basal glucose, insulin, insulin-to-C-peptide ratio (a measure of hepatic insulin extraction), insulin resistance index (derived from basal glucose and insulin levels), and glucose response after glucose challenge were higher in the offspring of diabetics of both races. The differences in insulin-to-C-peptide ratio and glucose response remained significant after adjusting for BMI; further, these two variables were independently associated with parental diabetes in both races. Waist-to-hip ratio, glucose response, C-peptide response (a measure of insulin secretion) were lower, and basal insulin-to-C-peptide ratio and postglucose suppression of free fatty acids greater in blacks versus whites, regardless of status of parental diabetes. Black-white differences in postglucose suppression of free fatty acids disappeared after adjusting for BMI. Thus, blacks and whites with parental type 2 diabetes show multiple abnormalities in parameters governing glucose homeostasis early in life, and some of these traits differ between the races, regardless of status of parental diabetes.     

Acute effect of ascorbic acid infusion on carbohydrate tolerance

Large doses (1 to 2g/3 hr) of ascorbic acid were administered intravenously to normal weight and obese, nondiabetic subjects. Glucose tolerance and fasting plasma glucose levels were unaffected, despite a 3- to 8-fold rise in plasma concentrations of the vitamin. Infusion of ascorbic acid did not alter fasting serum insulin levels in normal subjects, but was associated with lower concentrations of hormone during an intravenous glucose tolerance test. Plasma glucose, serum insulin, growth hormone, and glucagon levels in obese subjects remained unchanged during the ascorbic acid infusion.     

Effect of chlorpromazine on blood glucose and plasma insulin in man

In three groups of normal subjects and in one group of patients with latent diabetes mellitus a study has been made of the effects of chlorpromazine (CPZ) on blood glucose and plasma insulin. CPZ 75 mg/day for 7 days did not alter the plasma insulin response after oral glucose; nor did CPZ 50 mg/day for 7 days affect the glucose assimilation rate or insulin response to glucose injection. Infusion of CPZ 50 mg in 60 min slightly increased the basal blood glucose level but had no significant effect on basal plasma insulin. The insulin/glucose ratio after the end of the infusion was significantly higher than during the period of infusion of the drug. In latent diabetic patients CPZ infusion significantly diminished the insulin/glucose ratio during an intravenous glucose tolerance test. These results suggest that, whereas prolonged treatment with low doses of CPZ did not modify glucose tolerance and glucose-stimulated pancreatic response, higher acute doses of the drug may induce hyperglycaemia and can inhibit insulin secretion both in normal man and in patients with latent diabetes mellitus.     

Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women: modulation by cross-sex hormone administration

Increased plasminogen activator inhibitor type-1 (PAI-1) levels, leading to impaired fibrinolysis, are associated with increased visceral fat in middle-aged and obese subjects. It is unknown, however, whether this association is independent of other disturbances clustered in the insulin resistance syndrome. We analyzed this association in young, nonobese transsexual men and women before and after administration of cross-sex steroids, which potentially influence many elements of the insulin resistance syndrome, including PAI-1 levels and visceral fat accumulation. We assessed the visceral fat area (by MRI); total body fat; insulin sensitivity (with a glucose clamp technique); and plasma levels of PAI-1, insulin, and triglycerides in young (<37 years old), nonobese (body mass index <28 kg/m2), healthy men (n=18) and women (n=15) before and after 12 months of cross-sex hormone administration. Men were treated with ethinyl estradiol 100 microgram/d plus cyproterone acetate 100 mg/d, and women were treated with testosterone esters 250 mg IM every 2 weeks. At baseline, only visceral fat area was significantly correlated with plasma PAI-1 levels in both men (r=0.57, P=0.03) and women (r=0.59, P=0.03). In multivariate linear regression analysis, this association was independent of total body fat, insulin sensitivity, and plasma levels of triglycerides and insulin. After 12 months of cross-sex hormone administration, the plasma PAI-1 levels were no longer correlated with visceral fat (which had increased). We conclude that in young, nonobese men and women, visceral fat area is an important determinant of plasma PAI-1 levels. After cross-sex hormone administration, this association was no longer demonstrable.     

Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity. Eight obese (age 26+/-1 yr, body mass index 37+/-1 kg/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% from 16+/-1 to 28+/-4 ml/kg muscle . min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle . min (P < 0.05). However, this flow increase required twice as much bradykinin in the obese (51+/-3 microg over 100 min) than in the normal (25+/-1 mug, P < 0.001) subjects. In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28+/-4 ml/kg muscle . min) was comparable to that in the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle . min). Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/kg muscle . min) in the obese subjects. Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs. 56+/-9 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation. Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.     

Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects

To determine if both phases of glucagon secretion are excessive in diabetes, arginine was admimistered intravenously as pulses and as infusions to normal subjects, insulin-dependent diabetics, and noninsulin-requiring diabetics. The acute phase of glucagon secretion, in response to arginine pulses at four different doses (submaximal to maximal alpha-cell stimulating), was indistinguishable in terms of timing, peak levels attained, and total increments comparing controls and diabetics. During the first half of the arginine infusion (500 mg/kg over 30 min) the glucagon rise in controls and diabetics was similar (P greater than 0.1), whereas during the last half of the infusion excessive glucagon levels were seen in the diabetics. No difference in the glucagon responses to arginine administered as either a pulse or an infusion was observed between the two types of diabetics. The acute phase responses of insulin to intravenous, maximal stimulating doses of glucose (20 g) and arginine (2.5 g) were measured in five insulin-independent diabetics. Although the acute insulin response to arginine was normal, there was marked attentuation of the early beta-cell response upon stimulation by glucose. From these results we conclude that although in diabetes excessive glucagon levels are observed with chronic arginine stimulation, the acute phase of glucagon secretion in response to arginine is normal. In addition, the beta-cell in noninsulin-requiring diabetics, although acutely hyporesponsive to glucose, remains normally responsive to another stimulus, arginine.     

Docosahexanoic acid (DHA) improved glucose and lipid metabolism in KK-Ay mice with genetic non-insulin-dependent diabetes mellitus (NIDDM)

The hypoglycemic and hypolipidemic effect of docosahexaenoic acid (DHA; C22: 6omega-3) ethyl ester was examined in KK-Ay mice and neonatal streptozotocin-induced diabetic (NSZ) which are respectively obese and lean animal models of non-insulin-dependent diabetes mellitus (NIDDM), and in ddY normal mice. Single administration of DHA (500 mg/kg body weight) to KK-Ay mice significantly reduced (p<0.05) the blood glucose levels (BG) (p<0.05) and plasma free fatty acid levels (FFA) (p<0.05) at 10 h after oral administration when compared with control group. DHA (500 mg/kg body weight)-treated NSZ and normal mice, however, showed no change in these parameters. In addition, repeated administration of DHA (100 mg/kg) to KK-Ay mice significantly suppressed the increment of BG (p<0.05) and plasma triglyceride levels (TG) (p<0.01), and significantly decreased FFA (p<0.05) at 30 d compared with control group. DHA also significantly decreased the blood glucose at 60 and 120 min on insulin tolerance test (ITT). From these findings, it seems likely that DHA exhibits its hypoglycemic effects by increasing insulin sensitivity. It is concluded that DHA would be useful for treatment of obese type NIDDM with insulin resistance.     

Lipoprotein(a) in android obesity and NIDDM

OBJECTIVE: To assess the level of serum lipoprotein(a) [Lp(a)] in nonobese and obese NIDDM subjects with android body distribution. RESEARCH DESIGN AND METHODS: Serum Lp(a) levels were measured in 30 long-standing NIDDM patients (duration of diabetes 12.5 +/- 3 years, mean +/- SD), with 15 of the patients being obese of android distribution (BMI > 30 kg/m2 and waist-to-hip ratio > 0.8). In addition, there were 15 android obese nondiabetic subjects and 10 healthy subjects serving as the control group. RESULTS: All groups of patients in this study (diabetic, obese, and obese diabetic) showed significantly higher levels of Lp(a) than the healthy control group. Lp(a) concentrations were significantly higher in NIDDM patients with android type of obesity than in nondiabetic androids (24.1 +/- 5.6 vs. 14.8 +/- 2.4 mg/dl, P < 0.001). Significantly greater levels of Lp(a) were found in nonobese subjects with diabetes when compared with obese subjects without diabetes (22.3 +/- 4.1 vs. 14.8 +/- 2.4 mg/dl, P < 0.001). Furthermore, Lp(a) serum concentrations were not dependent on the degree of glycemic control (controlled NIDDM 23.6 +/- 5.0 vs. uncontrolled NIDDM 21.4 +/- 2.7 mg/dl, NS), but were much greater in subjects with diabetes complicated by vascular disease (complicated 26.3 +/- 5.0 vs. uncomplicated 20.5 +/- 2.7 mg/dl, P < 0.001). No correlation was found between Lp(a) and other lipid parameters in this study. CONCLUSIONS: Lp(a) levels are significantly elevated in both android-obese and nonobese NIDDM patients regardless of the degree of glycemic control. Lp(a) is an independent risk factor showing greater elevations in those subjects complicated with diabetic vascular diseases.     

Gastric inhibitory polypeptide (GIP) in maturity-onset diabetes mellitus

Serum GIP, insulin, and glucose concentrations were determined during a standard oral glucose tolerance test in 80 individuals, 45 of whom were normal and 35 of whom had adult-onset diabetes mellitus according to USPHS criteria. As a group, the diabetics had fasting hyperglycemia (219 +/- 17 mg./dl.) and, in response to glucose, displayed a peak serum glucose of 373 +/- 23 mg./dl. and sustained hyperglycemia (315 +/- 24 mg./dl.) at 180 minutes. There were no statistically significant differences in absolute serum insulin levels between the two groups. However, insulin secretion was delayed, IRI increments were smaller, and the IRI concentrations were inappropriately low for the simultaneous serum glucose concentrations in the diabetics at every time interval tested. Mean fasting serum GIP was 335 +/- 30 pg./ml. in the diabetics as against 262 +/- 15 pg./ml. in normal individuals (p less than 0.025). After the ingestion of glucose, diabetics had significantly higher (p less than 0.001) mean serum GIP levels between five and 120 minutes. By 180 minutes, serum GIP levels remained above fasting in both groups, but the diabetics had higher than normal serum concentrations (p less than 0.05). Peak serum GIP concentrations, which occurred at 30 minutes in both groups, were 1,376 +/- 106 and 806 +/- 75 pg./ml. in the diabetics and normals, respectively (p less than 0.001). Total integrated serum GIP was also greater in diabetics than normals (140,852 +/- 14,208 vs. 64,602 +/- 8,719 pg.-min./ml.-1, p less than 0.001). The higher serum GIP concentrations observed following glucose ingestion in diabetics could not be attributed to obesity or age. We conclude that both fasting and glucose-stimulated GIP concentrations are higher than normal in obese adult-onset diabetics. The significance of this observation is uncertain. However, since our current understanding suggests the GIP may be an important enteric signal for the release of insulin in man, and because GIP has been shown to stimulate the release of immunoreactive glucagon, GIP may play a role in the pathogenesis of diabetes mellitus.     

Feedback inhibition of insulin secretion and insulin resistance in polycystic ovarian syndrome with and without obesity

Hyperinsulinemia/insulin resistance is a well-known feature of polycystic ovarian (PCO) syndrome. In this study, the comparative roles of the peripheral tissues and the pancreatic beta-cells in its pathogenesis were evaluated. We determined basal serum C-peptide values (index of insulin secretion) and in vivo insulin action on peripheral glucose utilization (by the euglycemic hyperinsulinemic clamp technique) in obese (n = 5) and nonobese (n = 5) PCO women compared to obese (n = 5) and nonobese (n = 5) normal ovulatory women. During the clamp, feed-back inhibition of insulin on insulin secretion was studied by C-peptide percentage suppression. Serum C-peptide basal values did not differ significantly between the four groups. Insulin stimulated glucose utilization, expressed as M-value, was significantly decreased in both PCO groups compared to normal ovulatory women (p < 0.005). The metabolic clearance rate of glucose (MCR) and insulin (M/I) had the same behaviour. No differences were found between M, MCR and M/I values and the two groups of PCO subjects (obese/nonobese). The C-peptide percentage suppression was similar in all the groups. We conclude that PCO women have a significant insulin resistance that is independent of obesity, while basal and insulin-inhibited insulin secretion do not differ from normal-cycle subjects.     

Glucose tolerance in the elderly: the role of insulin and its receptor

Oral glucose tolerance tests were performed in young and elderly subjects with minimal risk factors for diabetes mellitus. Compared to the normal glucose tolerance in the young there was a 45% rate of impaired tolerance in the elderly. Fasting insulin levels were significantly lower in the elderly but post-glucose insulin responses in the first hour were similar in young and elderly subjects. Peripheral insulin action was assessed in terms of the 125 monoiodoinsulin binding to specific insulin receptor sites on circulating lymphocytes in the young, the elderly and a group of age and sex matched obese maturity-onset diabetics. Specific insulin binding was not significantly different in the elderly than in the young but was significantly lower in the diabetics than the young and the elderly. The results suggest that neither defective insulin binding are major causative factors in the reduced glucose tolerance of the elderly.     

Influence of physiologic hyperglucagonemia on basal and insulin-inhibited splanchnic glucose output in normal man

To evaluate the effects of physiologic hyperglucagonemia on splanchnic glucose output, glucagon was infused in a dose of 3 ng/kg per min to healthy subjects in the basal state and after splanchnic glucose output had been inhibited by an infusion of glucose (2 mg/kg per min). In the basal state, infusion of glucagon causing a 309 +/- 25 pg/ml rise in plasma concentration was accompanied by a rapid increase in splanchnic glucose output to values two to three times basal by 7-15 min. The rise in arterial blood glucose (0.5-1.5 mM) correlated directly with the increment in splanchnic glucose output. Despite continued glucagon infusion, and in the face of stable insulin levels, splanchnic glucose output declined after 22 min, returning to basal levels by 30-45 min. In the subjects initially receiving the glucose infusion, arterial insulin concentration rose by 5-12 muU/ml, while splanchnic glucose output fell by 85-100%. Infusion of glucagon causing an increment in plasma glucagon concentration of 272 +/- 30 pg/ml reversed the inhibition in splanchnic glucose production within 5 min. Splanchnic glucose output reached a peak increment 60% above basal levels at 10 min, and subsequently declined to levels 20-25% below basal at 30-45 min. These findings provide direct evidence that physiologic increments in plasma glucagon stimulate splanchnic glucose output in the basal state and reverse insulin-mediated inhibition of splanchnic glucose production in normal man. The transient nature of the stimulatory effect of glucagon on splanchnic glucose output suggests the rapid development of inhibition or reversal of glucagon action. This inhibition does not appear to depend on increased insulin secretio.