The dawn phenomenon does not occur in normal elderly subjects

To determine whether the dawn phenomenon occurs in normal elderly subjects and thus contributes to the progressive mild fasting hyperglycemia of aging, we examined the effect of physiological insulin levels on glucose disposal and hepatic glucose production (HGO) between 0530 and 0800 h, and 0930 and 1200 h. Paired euglycemic insulin clamp studies (8 mU/m2 X min) were performed on healthy old subjects (n = 5), employing [3H]glucose methodology to measure glucose production and disposal rates. Basal plasma insulin, GH, glucagon, and cortisol levels, and HGO and glucose disposal rates were similar before each study. Steady state plasma insulin values were slightly, but not significantly, lower during the dawn study [dawn: 20.3 +/- 1.1 (SE); control: 23.5 +/- 2.1 microU/ml, P = 0.08]. Insulin clearance rates were higher during the dawn study (dawn: 523 +/- 16; control: 430 +/- 19 ml/m2 X min, P less than 0.01). Maximum glucose disposal rates (dawn: 3.10 +/- 0.24; control: 3.03 +/- 0.23 mg/kg X min) and minimum HGO levels (dawn: 0.83 +/- 0.09; control: 0.62 +/- 0.03 mg/kg X min) were not significantly different in each part of the study. There was a significant decrease in plasma GH during the dawn (P less than 0.01, analysis of variance) but not the control studies. There was no difference in cortisol levels during the euglycemic clamp between the dawn and control studies. The mean decrement in glucagon during the insulin infusion was similar in each part of the study. We conclude that the dawn phenomenon does not occur in healthy elderly subjects despite an increase in insulin clearance during the dawn period.     

Feedback inhibition of insulin secretion is altered in cirrhosis

Hyperinsulinemia in human cirrhosis is generally considered an expression of reduced hepatic insulin degradation. To determine whether hyperinsulinemia may also depend on an altered feedback inhibition of insulin secretion, we performed euglycemic hyperinsulinemic clamp studies, infusing 40, 372, or 1280 mU/m2 X min biosynthetic human insulin in 30 compensated cirrhotic patients with portal hypertension and impaired glucose tolerance and 25 normal subjects, matched for age, sex, and weight. Mean fasting plasma insulin was significantly higher in cirrhotic patients [26.1 +/- 2.3 vs. 12.4 +/- 0.6 (+/- SE) microU/ml; P less than 0.001], while fasting plasma glucose levels were similar in the 2 groups. The mean plasma C-peptide level was significantly higher in cirrhotic patients, both basally (2.7 +/- 0.1 vs. 1.7 +/- 0.1 ng/ml; P less than 0.001) and during the clamp studies. Suppression of C-peptide at 120 min of the clamp was significantly less in cirrhotic patients (37 +/- 7% vs. 79 +/- 4%, 52 +/- 9% vs. approximately 100%, and 54 +/- 4% vs. approximately 100% during the 40, 372, and 1280 mU/m2 X min insulin infusions, respectively). The fasting C-peptide to insulin molar ratio was significantly lower in cirrhotic patients (5.4 +/- 0.3 vs. 6.4 +/- 0.3; P less than 0.005). The MCR of insulin at the three steady states was not significantly different between the 2 groups, whereas the basal systemic delivery rate of insulin was significantly higher in cirrhotic patients (14.7 +/- 1.7 vs. 6.5 +/- 0.4 mU/m2 X min; P less than 0.001). These results suggest that reduced feedback inhibition of insulin secretion may contribute to the hyperinsulinemia associated with cirrhosis.     

The physiological significance of the glucose intolerance of aging

Aging is associated with glucose intolerance, but its significance is unclear. We performed oral glucose tolerance tests and more physiologic meal tolerance tests in a group of 23 young adults, mean (+/- SE) age, 37 +/- 2 years and 17 elderly adults, mean age 69 +/- 1 years. The total glucose and insulin responses following the oral glucose load were increased by 24% and 127% respectively in the elderly compared with the young (24,524 +/- 1,080 vs. 19,734 +/- 702 mg/dl X min and 24,289 +/- 3,401 vs. 10,700 +/- 1,209 microU/ml X min). Following mixed meals, the total glucose response was 45,795 +/- 1,343 mg/dl X min in the young, compared with 50,998 +/- 1,850 mg/dl X min in the elderly (p less than .05) an 11% increase. Total insulin response was increased by 40% in the elderly (38,590 +/- 3,662 microU/ml X min) compared with the young (27,481 +/- 2,805 microU/ml X min) (p less than .05). We conclude that following the ingestion of more physiologic mixed meals, modest postprandial hyperglycemia and hyperinsulinemia can be demonstrated in elderly adults.     

Glucose and amino acid metabolism in aging man: differential effects of insulin

Insulin is a major regulator of glucose and body protein homeostasis, both of which demonstrate age-related changes. To clarify insulin's role in these age-related changes and to compare age-related glucose and protein homeostatic responses, insulin-mediated aspects of glucose and amino acid metabolism were simultaneously examined in healthy postabsorptive young (n = 5, mean age, 25 years) and elderly (n = 5, mean age, 76 years) men. Primed constant infusions of L-[1-13C]leucine and L-[15N]alanine were administered during a basal period (0 to 180 minutes) and during four separate single rate euglycemic insulin infusions (180 to 360 minutes). Steady state insulin concentrations were 16 +/- 1, 29 +/- 3, 75 +/- 5, and 2407 +/- 56 microU/mL in the young and 23 +/- 4, 37 +/- 8, 96 +/- 11 and 3,357 +/- 249 microU/mL in the elderly at the different insulin infusion rates of 6, 10, 30, and 400 mU mU.m-2.min-1, respectively. For the 6 and 10 mU insulin infusion rates, a primed, constant infusion of [6,6 - 2H2]glucose permitted quantitation of hepatic glucose production. Glucose disposal rates adjusted for lean body mass (LBM) were lower in the elderly than in the young at the 6, 10, and 30 mU insulin infusion rates and similar in the two age groups in the 400 mU studies. Insulin dose-dependent reductions occurred in eight of ten plasma amino acids and were not influenced by age. There was an insulin dose-dependent reduction in plasma leucine flux which was similar in both age groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Counterregulatory responses to insulin-induced glucose reduction in the elderly

The impact of age on counterregulatory responses to moderate reductions in blood glucose induced by a constant insulin infusion (20 mU/m2 X min) was studied in normal young (n = 7; aged 20-42 yr) and old (n = 7; aged 66-77 yr) nonobese subjects. Insulin was infused until the whole blood glucose level fell to or below 60 mg/dl. This required an infusion time of 39 +/- 3 (+/- SE) min in the young and 36 +/- 3 min in the old. Mean basal glucose [young, 88 +/- 2 (+/- SE); old, 88 +/- 2 mg/dl), minimum glucose (young, 51 +/- 2; old, 54 +/- 1 mg/dl), time to nadir (young, 48 +/- 3; old, 44 +/- 3), and time to recovery were similar in both groups. Maximal (young, 40.3 +/- 2.3; old, 42.1 +/- 3.3 microU/ml) insulin levels were also similar. Basal and maximal levels of glucagon, epinephrine, and GH were similar in the two groups. Although basal norepinephrine values were higher in the old subjects (young, 243 +/- 38; old, 364 +/- 23 pg/ml; P = 0.02), increments above basal during reduction in blood glucose were not affected by age. Basal cortisol values were similar (young, 13.7 +/- 1.4; old, 14.0 +/- 0.7 micrograms/dl), but maximum cortisol responses were slightly greater in the old subjects (young, 14.6 +/- 1.0; old, 17.7 +/- 0.9 micrograms/dl; P = 0.03). These studies indicate that hormonal responses and counterregulatory efficiency during modest reductions in blood glucose are preserved in healthy elderly subjects.     

Modulation of insulin secretion by insulin and glucose in type II diabetes mellitus

We studied the dose-response characteristics of insulin's ability to modulate its own secretion in normal and type II diabetic (NIDDM) subjects by measuring suppression of serum C-peptide levels during insulin infusions with the plasma glucose level held constant. In normal subjects at euglycemia, primed continuous insulin infusion rates of 15, 40, 120, and 240 mU/M2 X min acutely raised serum insulin to steady state levels of 37 +/- 2 (+/- SE), 96 +/- 6, 286 +/- 17, and 871 +/- 93 microU/ml, respectively. During each infusion, maximal suppression of C-peptide to 30% of basal levels occurred by 130 min. At the higher insulin levels (greater than or equal to 100 microU/ml), C-peptide levels fell rapidly, with an apparent t1/2 of 13 min, which approximates estimates for the t1/2 of circulating C-peptide in man. This is consistent with an immediate 70% inhibition of the basal rate of insulin secretion. At the lower insulin level (37 +/- 2 microU/ml), C-peptide levels fell to 30% of basal values less rapidly (apparent t1/2, 33 min), suggesting that 70% inhibition of basal insulin secretion rates was achieved more slowly. In NIDDM subjects, primed continuous insulin infusion rates of 15, 40, 120, and 1200 mU/M2 X min acutely raised serum insulin to steady state levels of 49 +/- 7, 93 +/- 11,364 +/- 31, and 10,003 +/- 988 microU/ml. During studies at basal hyperglycemia, only minimal C-peptide suppression was found, even at pharmacological insulin levels (10,003 +/- 988 microU/ml). However, if plasma glucose was allowed to fall during the insulin infusions, there was a rapid decrease in serum C-peptide to 30% of basal levels, analogous to that in normal subjects. Three weeks of intensive insulin therapy did not alter C-peptide suppression under conditions of hyperinsulinemia and falling plasma glucose. The following conclusions were reached. 1) In normal subjects, insulin (40-1000 microU/ml) inhibits its own secretion in a dose-responsive manner; more time is required to achieve maximal 70% suppression at the lower insulin level (40 microU/ml). 2) In NIDDM studied at basal hyperglycemia, insulin has minimal ability to suppress its own secretion. Thus, impaired feedback inhibition could contribute to basal hyperinsulinemia. 3) Under conditions of hyperinsulinemia and falling plasma glucose, insulin secretion is rapidly suppressed in NIDDM (analogous to that in normal subjects studied during euglycemia.     

Lack of in vivo insulin resistance in controlled insulin-dependent, type I, diabetic patients

Although type I diabetic patients are clearly insulin deficient, it is unclear whether they have normal in vivo sensitivity to insulin. Recent studies which suggested that insulin resistance is a common feature of insulin-dependent diabetics have not taken into account their degree of metabolic control or the presence of circulating antibodies. In the present study, we performed multiple euglycemic glucose clamp studies to construct insulin dose-response curves in 5 well controlled and 5 poorly controlled type I diabetic patients and 21 age-matched normal subjects. Each study was performed on a separate day at insulin infusion rates of 15, 40, 120, 240, or 1200 mU/M2 X min. During the 40 and 120 mU/M2 X min infusions, steady state insulin levels of 96 +/- 8 (+/- SE) and 285 +/- 27 microU/ml respectively, were achieved within 25 min in normal subjects. In contrast, diabetic subjects did not achieve steady state insulin levels (62 +/- 8 and 212 +/- 16 microU/ml) until 90 min of infusion, and insulin antibodies were detectable in the serum of all these patients. The dose-response curve for insulin stimulation of glucose disposal in well controlled diabetic subjects was comparable to that in normal subjects, with half-maximally effective insulin levels of 84 microU/ml in the diabetic patients compared to 70 microU/ml in normal subjects and virtually identical maximal rates of glucose disposal (433 +/- 11 vs. 411 +/- 17 mg/M2 X min in controls). In contrast, the dose-response curve for poorly controlled diabetic subjects was significantly right-shifted (half-maximally effective insulin level, 112 microU/ml), with marked reduction in the maximal glucose disposal rate (324 +/- 25 vs. 411 +/- 17 mg/M2 X min in normal subjects). Basal hepatic glucose output was increased in both poorly controlled and well controlled type I diabetic patients (132 +/- 7 and 101 +/- 16 mg/M2 X min, respectively) compared to normal subjects (76 +/- 7 mg/M2 X min). However, during each insulin infusion, hepatic glucose output was virtually 100% suppressed in all 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

Glucose-dose dependent characteristics of insulin secretion in obese and lean sheep

We previously reported that obesity in sheep and cattle was associated with basal hyperinsulinemia, insulin resistance, and an exaggerated insulin response to a single dose (350 mg/kg) of glucose. In this study, the glucose-dose dependency of insulin secretion in obese and lean sheep was determined by 1) using jugular venous concentrations of insulin (Exp 1) and 2) arteriovenous differences in insulin concentrations across the pancreas together with plasma flow rates in the portal vein (Exp 2). Sheep were injected with glucose doses of 0 (water), 10, 30, 100, and 350 mg glucose/kg body weight in Exp 1 (six sheep per group) and with a low (20 mg/kg) and high (200 mg/kg) dose of glucose in exp 2 (four sheep per group). In Exp 1, mean (+/- SE) pretreatment plasma concentrations of insulin (22.0 +/- 1.7 vs. 9.4 +/- 0.4 microU/ml) and glucose (56.1 +/- 0.5 vs. 52.4 +/- 0.8 mg/dl) were greater (P less than 0.01) in obese than lean sheep fasted for 12 h. The glucose-induced rises in insulin concentrations above pretreatment levels were always greater (P less than 0.05) in obese than lean sheep regardless of glucose dose. Eadie-Scatchard plot analysis of the hyperbolic relationship between the acute insulin and acute glucose response areas (0 to +10 min) indicated that the maximum (Vmax) early phase insulin response was greater (P less than 0.025) in obese than lean sheep (568 +/- 148 vs. 156 +/- 33 microU ml-1 X min). In Exp 2, pretreatment concentrations of insulin (25.1 +/- 3.4 vs. 5.6 +/- 1.2 microU/ml) and glucose (58.3 +/- 1.8 vs. 45.5 +/- 1.1 mg/dl) in arterial plasma were greater (P less than 0.01) in obese than in lean sheep fasted 18 to 22 h. Similarly, pretreatment pancreatic secretion rates of insulin were greater (P less than 0.01) in obese (17.8 +/- 5.8 mU/min) than in lean (4.9 +/- 1.3 mU/min) sheep. Glucose-induced acute (0 to +10 min) increments in pancreatic secretory rates of insulin also were greater (P less than 0.05) in obese than in lean sheep after the low (215 +/- 73 vs. 11 +/- 15 mU) and high (881 +/- 281 vs. 232 +/- 66 mU) doses of glucose. It was concluded that insulin secretion in response to a range of stimulatory concentrations of glucose was greater in obese than in lean sheep because the obese sheep had greater maximum (i.e. Vmax) acute phases of glucose-induced insulin secretion.     

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.     

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.     

The effects of euglycemic hyperinsulinemia and amino acid infusion on regional and whole body glucose disposal in man

We investigated the effects of amino acid infusion on regional and whole body glucose metabolism in 16 normal volunteers, age 32 to 70 years. Ten subjects underwent 140-minute euglycemic insulin infusions at the rate of 1 mU/kg.min with concomitant 10% amino acid infusion. Six volunteers who underwent identical euglycemic insulin infusions without amino acid infusion served as controls. Whole body glucose disposal was estimated by the rate of exogenous glucose infusion required to maintain euglycemia, and peripheral glucose balance was evaluated by the forearm balance technique. In four subjects from each group, a primed, continuous infusion of [3-3H]glucose was used to quantify endogenous glucose production (EGP). Comparable states of hyperinsulinemia were achieved with insulin concentrations (microU/mL) of 101 +/- 7 observed in the group with amino acid infusion and 95 +/- 14 in the control group. Whole body glucose utilization was significantly lower (P less than .001) in the subjects receiving amino acid infusion (5.0 +/- 0.4 mg/kg.min) compared with the control group (8.7 +/- 0.8 mg/kg.min). Forearm glucose disposal was markedly reduced (P less than .05) in the group receiving amino acid infusion (1,385 +/- 330 nmol/100 g.min) compared with controls (2,980 +/- 460 nmol/100 g.min). Under comparable conditions of euglycemia and hyperinsulinemia, virtually complete suppression of EGP was observed in both groups. We conclude that infusion of amino acids with insulin under euglycemic conditions reduces whole body glucose utilization primarily by reducing peripheral glucose disposal.     

Effects of short-term pulsatile and continuous insulin delivery on glucagon secretion and insulin secretion and action

In six normal nonobese subjects, hyperinsulinemic euglycemic clamps were performed during paired sequential two-hour intravenous (IV) insulin infusions separated by an hour washout period. Each infusion was either 32 mU/kg/h of continuous insulin (CI) or 75% of this dose as 40-second pulses delivered every 13 minutes (PI). Six studies were performed with each of the following sequences in random order: PI-CI, CI-PI, and CI-CI. Based on the initial infusions, the insulin-dependent fractional glucose disappearance rate (X) during pulsatile insulin delivery (3.0 +/- 0.4 min-1 X 10(2), n = 6) was 73% of that of the continuous infusions (4.1 +/- 0.3 min-1 X 10(2), n = 12). This ratio was similar to that of the measured time-averaged plasma insulin areas (PI = 24.7 +/- 3.8 v CI = 31.4 +/- 3.5 mU/L). There was an average 23% enhancement of insulin's hypoglycemic effect during the second 12 CI infusions compared with the 12 initial CI infusions (X = 5.1 +/- 0.5 v 4.1 +/- 0.3 min-1 X 10(2), P less than .05). There was no significant difference between the enhancing effects of PI and CI infusions on insulin action in the subsequent CI's (X = 4.9 +/- 0.9 for PI-CI v X = 5.3 +/- 0.2 min-1 X 10(2) for CI-CI). First infusion PI significantly (P less than .05) decreased plasma C-peptide levels (0.34 +/- 0.05 to 0.20 +/- 0.06 mumol/L), whereas CI did not (0.33 +/- 0.02 to 0.32 +/- 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of obesity on susceptibility to fatty acid-induced peripheral tissue insulin resistance

Elevation of plasma nonesterified fatty acid (NEFA) levels has been shown to impair the actions of insulin on peripheral glucose uptake and suppression of hepatic glucose output (HGO). These studies have been conducted almost exclusively in healthy, lean men. We therefore set out to test the hypothesis that obese subjects, because they are already insulin-resistant, are less susceptible than lean subjects to the inhibitory effects of elevated NEFA on insulin-stimulated glucose disposal. We studied 15 lean (11 men, 4 women; age, 45 +/- 3 years [mean +/- SE]; body mass index [BMI], 22.7 +/- 0.6 kg/m(2)) and 15 obese normal subjects (11 men, 4 women; 49 +/- 3 years; 31.7 +/- 1.0 kg/m(2)). Each subject underwent two 5-hour 80-mU/m(2)/min hyperinsulinemic euglycemic clamps with measurement of glucose kinetics (intravenous 3-(3)H-glucose). Plasma NEFA levels were elevated in one study for 3 hours before and during the clamp ( approximately 1 mmol/L in both groups) by infusion of 20% Intralipid (60 mL/h) and heparin (900 U/h). The obese subjects had higher fasting insulin levels (9.1 +/- 1.1 v 4.8 +/- 0.6 mU/L, P <.005) and were insulin-resistant (glucose disposal rate [GDR] at the end of the control glucose clamps: obese, 7.96 +/- 0.55, lean, 10.24 +/- 0.35 mg/kg/min, P <.002). Contrary to our hypothesis, elevation of plasma NEFA had a similar effect in the lean and obese subjects, both in terms of the absolute reduction of insulin stimulated GDR in the lean (1.82 +/- 0.36 mg/kg/min decrement) and obese subjects (2.03 +/- 0.37 mg/kg/min decrement) and the overall percentage reduction in GDR (lean, 17.1% +/- 3.1%; obese, 24.5% +/- 4.2%; difference not significant [NS]). Suppression of HGO during the lipid clamps was also impaired to a similar extent in the 2 groups. Findings were similar for the 9 obese subjects with a BMI of 30 kg/m(2) or more. Combining the 2 groups, the NEFA induced reduction of insulin stimulated GDR did not correlate with BMI (r = 0.08, NS) or with insulin sensitivity (GDR) measured in the control study (r = 0.11, NS). In summary, the effect of a short term elevation of plasma NEFA levels on insulin stimulated GDR and suppression of HGO is comparable in lean and moderately obese subjects.     

In vivo insulin action in type 1 (insulin-dependent) diabetic pregnant women as assessed by the insulin clamp technique

To determine the influence of pregnancy on insulin sensitivity in patients with type 1 diabetes mellitus in more detail, a hyperinsulinemic euglycemic clamp study was performed in six pregnant type 1 diabetic women and eight nonpregnant women with type 1 diabetes mellitus. All of the pregnant women were studied three times: in early pregnancy (mean, week 13), late pregnancy (mean, week 34), and within a week after delivery. Insulin was infused in a constant rate of 1.0 mU/kg X min, which resulted in steady state serum free insulin levels (I) of 44 +/- 3 (+/- SEM), 56.6 +/- 6, and 55 +/- 8 microU/ml in the pregnant diabetic women and 52 +/- 4 microU/ml in the nonpregnant women. Mean glucose disposal (M) was 5.6 +/- 0.3 mg/kg X min early in pregnancy and 3.4 +/- 0.5 mg/kg X min late in pregnancy (P less than 0.02). However, in the early postpartum period, M was again higher (7.2 +/- 0.7 mg/kg X min; P less than 0.02) and similar to values in early pregnancy and nonpregnant diabetic women (7.2 +/- 0.6 mg/kg X min). When tissue sensitivity to insulin was expressed as the M to I ratio, similar results were obtained (nonpregnant women, early stage of gestation, and postpartum vs. late stage of gestation: 0.13 +/- 0.01, 0.13 +/- 0.01, and 0.15 +/- 0.03 mg/kg X min per microU/ml vs. 0.06 +/- 0.1 mg/kg X min per microU/ml; P less than 0.03 in all). There tended to be an inverse relationship between serum levels of human placental lactogen and the M to I ratio during pregnancy (r = -0.74; P = 0.09). However, we found no association between changes in the impairment of insulin action and serum estradiol, progesterone, or cortisol levels. In conclusion, pregnant type 1 diabetic women have insulin resistance in peripheral tissues in the late stage of gestation. Insulin sensitivity returns to values found in nonpregnant diabetic women within the first week after delivery.     

How insulin resistant are patients with noninsulin-dependent diabetes mellitus?

The study was carried out to quantify the ability of physiological increases in the plasma insulin concentration to stimulate glucose disposal above basal levels in 25 normal subjects and 25 patients with noninsulin-dependent diabetes mellitus (NIDDM). Patients were sex, age, and weight matched, and glucose disposal was determined under basal conditions (plasma insulin, approximately 10 microU/ml) and after plasma insulin levels had been increased to approximately 90 microU/ml. The mean (+/- SEM) glucose disposal rate was significantly greater (P less than 0.001) under basal conditions in patients with NIDDM (110 +/- 5 mg/m2 X min) than in individuals with normal glucose tolerance (77 +/- 4 mg/m2 X min). Glucose disposal rates increased in both normal subjects and NIDDM patients when plasma insulin concentrations were increased to about 90 microU/ml; however, the increment was much greater in normal subjects. Thus, glucose disposal only rose to a mean (+/- SEM) value of 145 +/- 7 mg/m2 X min in patients with NIDDM, representing an approximate 30% increase due to insulin. In contrast, a similar elevation of plasma insulin in normal subjects resulted in an increase in glucose disposal of approximately 300%, reaching a mean (+/- SEM) value of 310 +/- 24 mg/m2 X min. These results indicate that the defect in insulin-stimulated glucose uptake is significantly greater in patients with NIDDM than has previously been found.     

Contrasting effects of L-arginine on insulin-mediated blood flow and glucose disposal in the elderly

Insulin increases skeletal muscle blood flow in healthy young subjects by a nitric oxide (NO)-dependent mechanism. Impairment of this mechanism may contribute to the insulin resistance of normal aging. We tested the hypothesis that L-arginine, the endogenous precursor for NO synthesis, would augment insulin-mediated vasodilation and in so doing increase insulin-mediated glucose uptake (IMGU) in healthy elderly subjects. Experiments were conducted on healthy young (n = 9; age, 24 +/- 1 years; body mass index, 24 +/- 1 kg/m2) and old (n = 9; age, 77 +/- 2 years; BMI, 25 +/- 1 kg/m2) subjects. Each underwent two euglycemic clamp studies. On both occasions, insulin was infused from 0 to 120 minutes (young, 40 mU/m2/min; old, 34 mU/m2/min). On 1 day, insulin was continued and L-arginine (7.5 mg/kg/min) was coinfused from 120 to 240 minutes. On the second study day, the insulin infusion from 120 minutes onward was adjusted in each subject to match corresponding plasma concentrations during the L-arginine infusion. Calf blood flow was measured bilaterally using venous occlusion plethysmography. Mean arterial blood pressure decreased in response to L-arginine in both young (77 +/- 1 v 73 +/- 1 mm Hg; P < .05) and old (103 +/- 2 v 94 +/- 2 mm Hg; P < .01). Calf vascular conductance increased in young (from 0.094 +/- 0.009 to 0.113 +/- 0.012 mL/100 mL/min/mm Hg; P < .01) and old (from 0.035 +/- 0.003 to 0.050 +/- 0.003 mL/100 mL/min/mm Hg; P < .01), consistent with the concept that the addition of substrate can augment skeletal muscle endothelial NO production in both age groups. Calf blood flow increased in both young (control, 7.04 +/- 0.73; L-arginine, 8.02 +/- 0.78 mL/100 mL/min; P < .05) and old (control, 3.60 +/- 0.27: L-arginine, 4.65 +/- 0.23 mL/100 mL/min; P < .0001) subjects, yet L-arginine had no impact on glucose disposal in either age group. In conclusion, L-arginine caused skeletal muscle vasodilation in the elderly, indicating that this endothelially mediated response is not attenuated with age. However, this increase in blood flow had no impact on insulin-mediated glucose uptake.     

Fetal plasma insulin and thyroid hormone levels during acute in utero ethanol exposure in a maternal-fetal sheep model

The effects of acute in utero ethanol (ETOH) treatment on basal and stimulated thyroid and insulin levels in fetal plasma were studied in chronically cannulated fetal sheep. In test situations, pregnant ewes (0.78-0.88 gestation) which were chronically cannulated received 2 g/kg ETOH [25% (vol/vol) in isotonic saline] for 2 h; this was followed by a maintenance iv infusion of 0.13 g/kg ETOH. Control animals received isovolemic infusions of isotonic saline. Fetal arterial plasma samples were obtained after the 2-h infusion, and basal levels of T3, T4, glucose, and insulin were measured. The 2-h ETOH infusion did not influence fetal basal plasma T3, T4, insulin, or glucose. Fetal thyroid responses to an intraarterial injection of 0.01, 0.10, 1.00, or 10.00 micrograms/kg TRH or of 5 mU/kg TSH through the fetal catheters were studied in the presence or absence of high plasma ETOH concentrations. Fetal T4 or T3 levels during the 4 h following any of these stimuli were not significantly different in ethanol-treated and control animals. The effects of acute ETOH exposure on insulin responses to a glucose challenge were studied in six chronically cannulated ewes and their fetuses using a cross-over experimental design. After the 2-h ETOH infusion, ewes received a bolus injection of 600 mg/kg 50% glucose, followed by a 1-h infusion of 624 mg/kg 50% glucose and 0.13 g/kg ETOH. In control situations, ewes received saline plus glucose. Acute ETOH treatment did not influence maternal or fetal plasma glucose levels at any time, but enhanced both maternal and fetal insulin responses to glucose. Total insulin release, as measured by the area under the insulin response curve, was greater during ETOH exposure in both mother (ETOH, 4740 +/- 1475 microU/ml X min; control, 2807 +/- 766 microU/ml X min; P = 0.05) and fetus (ETOH, 562 +/- 94 microU/ml X min; control, 363 +/- 46 microU/ml X min; P less than 0.05). Thus acute in utero ETOH exposure does not diminish plasma levels of either thyroid hormones or insulin, two important hormones for fetal growth and development. However, ethanol exposure enhances the insulin response to increases in blood glucose in both mother and fetus.     

Similar effects of pulsatile and constant intravenous insulin delivery

Effects of constant and pulsatile i.v. insulin delivery were examined in seven healthy subjects by means of euglycemic clamp technique. Each subject received constant insulin infusion (0.175 mU/kg.min) or insulin pulses at 12-min intervals (2.1 mU/kg) in randomized order for 8-h periods (08.00-16.00 h). Endogenous secretion of insulin was inhibited by concomitant administration of somatostatin (300 micrograms/h). Serum insulin concentrations during constant infusion (12 +/- 1 microU/ml) did not differ from basal values (11 +/- 1 microU/ml). Pulsatile insulin delivery resulted in oscillations of mean concentrations between values of about 10 and 20 microU/ml. Mean blood glucose concentrations during experiments were kept at 80 +/- 1 mg/dl, irrespective of the mode of insulin administration. Moreover, dextrose requirements for maintenance of these glucose concentrations did not differ over the hole periods of examination. We conclude that effects of constant and pulsatile delivery of basal amounts of insulin are not different. This at least applies to peripheral, short-term insulin administration in somatostatin-treated normal man, during an euglycemic clamp.     

Splanchnic factors enhance the norepinephrine response to oral glucose in aged man

Oral glucose has been shown to increase sympathetic nervous system (SNS) activity more in old than in young subjects. In contrast intravenous glucose during euglycemic hyperinsulinemia increases SNS activity in young but not in old subjects. To evaluate the role of splanchnic factors in this discrepancy, we employed a modification of the glucose clamp technique in 6 young (24-39 years) and 8 old (65-83 years) normal males. Each subject underwent two studies in which insulin was infused at 120 mU/m2 X min for 3 h and either oral glucose (50 gms) or water was given 60 min after initiating insulin. Euglycemia was maintained in all studies. When compared to control drink, oral glucose elevated norepinephrine in old (p less than 0.01), but not in young subjects. The difference between old and young was significant (p less than 0.02). When compared to control drink, oral glucose increased pulse rate and double product in the young, and pulse rate in the old. These results indicate that oral glucose activates the SNS in the elderly via splanchnic mechanisms independent of changes in circulating levels of glucose or insulin.     

The effect of age and glucose concentration on insulin secretion by the isolated perfused rat pancreas

Age changes in the beta-cell's sensitivity to glucose as well as in its overall capacity to secrete insulin may play a part in the glucose intolerance of aging. The isolated perfused rat pancreas preparation was used to study the effect of age and glucose level on insulin secretion. Overnight-fasted male Wistar 12- and 23-month-old rats had basal plasma glucose levels of 106 +/- 4 (SE) and 100 +/- 4 mg/dl. Perfusate glucose levels were raised from 80 mg/dl to either 150, 220, or 360 mg/dl for 50 min (n = 6 to 8 in each group). Insulin secretion followed the typical biphasic pattern of an early spike and fall, followed by a sustained gradual increase at both ages. First-phase (0-10 min) insulin secretion in the old rats was significantly lower at 150 (184 vs. 524 microU/min, P less than 0.05) and 220 mg/dl (327 vs. 644 microU/min, P less than 0.05), while it was nearly identical at 360 mg/dl. Although lower in the old rats, second-phase (11-50 min) insulin secretion was not statistically significantly different for each glucose level. When first- and second-phase insulin secretion rates were combined, the old rats' insulin secretion was only lower at the 150 mg/dl level (248 vs. 426 microU/min, P less than 0.05). Thus, at the more physiological glucose level, old rats showed a significantly lower response, while at the higher levels insulin secretion was similar. This diminishing age effect with increasing glucose dose suggests a defect in islet sensitivity to glucose rather than a diminished capacity to secrete insulin.