Effects of hypertonicity on water intake in the elderly: an age-related failure.

Dehydration is a common clinical syndrome associated with many illnesses and treatments in the elderly. Prior studies have shown diminished sensation of thirst during water deprivation. It is currently unclear whether age-related decreases in thirst perception impair the defense against a hyperosmolar challenge. To examine the impact of water ingestion during hyperosmolality, young and old subjects were allowed free access to water during and after an intravenous infusion of 5% hypertonic saline. Cumulative water intake and serum osmolality were compared between seven healthy young (20-28 yrs) and seven healthy old (72-89 yrs) volunteers during and following a two hour hypertonic saline infusion at a rate of 0.06 mlxkg(-1) min(-1). Serum osmolality and water intake were markedly different between the two groups. In the old group, serum osmolality increased by 17 mosmol/kg above baseline despite free access to water. In contrast, serum osmolality increased to only 7 mosmol/kg above baseline in the young group and did not rise further. By ingesting water, the young were able to defend against an additional increase in serum osmolality. The young drank approximately twice that of the old during the infusion period. Healthy older individuals drink less than young despite a significantly increased serum osmolality. This hypodipsia in old individuals increases their susceptibility to hypertonicity.

The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects.

Despite similar glycemic profiles, higher insulin levels are achieved following oral versus intravenous administration of glucose. This discrepancy is due to the incretin effect and is believed to be mediated via stimulation of beta-cells by hormone(s) released from the gut. The leading gut hormone candidates are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). To determine the relative insulinotropic activity of these peptides, we infused GLP-1(7-37) and GIP into normal subjects and patients with non-insulin dependent diabetes mellitus (NIDDM). In normal subjects during euglycemia, GLP-1(7-37) stimulated insulin release, whereas GIP did not. Using the Andres clamp technique, we established stable hyperglycemia for 2 h (5.4 mmol/l above the basal level). During the second hour, either GIP, GLP-1(7-37), or both were infused in normal healthy volunteers and in patients with NIDDM. In normal subjects, at a glucose level of 10.4 mmol/l, the 90-120 min insulin response was 279 pmol/l. GIP at a dose of 1, 2 or 4 pmol/kg/min augmented the 90-120 min insulin response by 69, 841 and 920 pmol/l, while GLP-1(7-37), at a dose of 1.5 pmol/kg/min augmented the insulin response by 2106 pmol/l. When both hormones were administered simultaneously, the augmentation was additive--2813 pmol/l. In the diabetic subjects, GIP had no effect, while GLP-1(7-37) augmented the insulin response by 929 pmol/l. We conclude that in normal healthy subjects, GLP-1(7-37), on a molar basis, is several times more potent than GIP at equivalent glycemic conditions. The additive insulinotropic effect suggests that more than one incretin may be responsible for the greater insulin levels observed following oral administration of glucose compared to the intravenous route. In NIDDM, GIP had no insulinotropic effect, while GLP-1(7-37) had a marked effect. This suggests that GLP-1(7-37) may have therapeutic potential as a hypoglycemic agent in NIDDM patients.

Effects of recombinant human IGF-I on glucose and leucine kinetics in men.

To examine the effects of recombinant human (rh) insulin-like growth factor I (IGF-I), insulin, and saline on metabolic parameters, we studied 20 young nonobese healthy men. Euglycemic clamps with 240-min IGF-I infusions at two doses (49 and 33 pmol.kg-1 x min-1, n = 8 and 12 subjects) were performed and compared with hyperinsulinemic-euglycemic clamps (2.25 pmol.kg-1 x min-1, n = 9). Leucine and glucose kinetics were examined with L-[1-13C]leucine and [3-3H]glucose. Glucose rate of appearance (Ra) declined equivalently in the 49 pmol.kg-1.min-1 IGF-I and insulin clamps but remained at basal levels during the 33 pmol.kg-1 x min-1 IGF-I infusions. In contrast, Rd of glucose was increased by 176% in the 49 pmol.kg-1 x min-1 IGF-I and 78% in the 33 pmol.kg-1 x min-1 IGF-I infusions. Furthermore, to prevent hypoglycemia after the termination of both rhIGF-I infusions, it was necessary to infuse glucose for an additional 2-20 h. Ra of leucine was suppressed significantly by both IGF-I and insulin, whereas leucine oxidation was not affected by either hormone. Therefore, the rate of disappearance of leucine expressed as the difference between Ra and oxidation rates was significantly reduced in all clamps. In addition, IGF-I significantly suppressed beta-cell secretion without affecting the other glucoregulatory hormones. In contrast to insulin, IGF-I had no apparent effect on lipolysis, as measured by changes in nonesterified fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of age on insulin response and glucose utilization during four hyperglycemic plateaus.

In order to evaluate the potential role of insulin insensitivity as a cause of the glucose (G) intolerance of aging, we performed 230 hyperglycemic clamps, 85 on young (Y, 24 to 39 years), 47 on middle age (M, 40 to 59 years), and 98 on old (O, 60 to 90 years) carefully screened subjects of the Baltimore Longitudinal Study of Aging. The 2-h plasma G levels on an oral glucose tolerance test (OGTT) were < 7.8 mmol/l in Y and M and < 10 mmol/l in old; the latter group was further dichotomized at 7.8 mmol/l into a "normal" group, ON, and an impaired group, OI. Four hyperglycemic plateaus were created: 3.0, 5.4, 7.9, and 12.8 mmol/l above basal. Three measures of glucose tolerance--1) G at 2 h after glucose ingestion, 2) glucose utilization, M, at each hyperglycemic plateau, and 3) glucose decay constant, K, obtained at the conclusion of each clamp--showed the best performance in the young group (Y > M = ON > OI). Despite these differences in glucose tolerance, plasma insulin responses (I) during the clamp were not significantly different except that ON < Y at the basal + 12.8 plateau (300 +/- 42 vs. 456 +/- 48 pmol/l, p < 0.01). Insulin-dependent glucose uptake, a measure of tissue sensitivity to insulin, was decreased in the old-impaired group at every plateau except the highest. We conclude that healthy, active older subjects showed moderate intolerance to oral and IV glucose and that the mechanism of this physiological aging process is most likely decreased insulin sensitivity.

The pituitary-adrenal glucocorticoid response is altered by gender and disease.

BACKGROUND: This study examined the role of age, gender, and disease in the regulation of the pituitary-adrenal axis. METHODS: Serum cortisol and immunoreactive corticotropin (ACTH) were measured for five hours after a bolus administration of ovine corticotropin releasing hormone (oCRH, 1 microgram/kg) during three separate investigations: 1) age: comparison was made between young men (26 +/- 3 years [means +/- SE]) vs old men (73 +/- 2 years); 2) gender: comparison between old men (73 +/- 2 years) vs old women (68 +/- 3 years); and 3) disease: comparison was made between healthy subjects (no disease, 44 +/- 6 years) vs subjects with a chronic stable disease (diabetes mellitus [DM] or hypertension [HBP], 48 +/- 5 years). RESULTS: Basal concentrations of cortisol were significantly higher in younger men (127 +/- 17 vs 74 +/- 11 nmol/L, p < .03), as were peak cortisol levels (499 +/- 30 vs 397 +/- 36 nmol/L, p < .05, ANOVA). However, the 5-hour nadir of cortisol, area under the curve, delta area under the curve, time to peak, and variability of the responses during three separate admissions were similar in young and old. When the responses to oCRH in old men and old women were compared, old women had significantly higher basal values of cortisol (163 +/- 30 vs 75 +/- 11 nmol/L, p < .02), peak levels of cortisol (p < .0001) and the 5-hour nadir of cortisol was 124% higher in older women (657 +/- 61 vs 298 +/- 50 nmol/L, p < .0006). When the response to oCRH was examined in healthy subjects and subjects with disease (DM and HBP), men with disease had a peak cortisol response 40% higher (p < .003) than healthy men and the level remained 85% higher (p < .0005) at 5 hours. The responses of ACTH to oCRH were not different in the groups being compared for any study. The variation of cortisol response could be explained by the peak cortisol levels (R2 = .718, p < .0001), with a small significant contribution from disease (R2 = .013, p < .002). In summary, the adrenal response to oCRH remained elevated throughout the period of study in elderly women. In addition, subjects with a chronic disease (DM and HBP) had a greater response of cortisol to oCRH compared with healthy subjects. CONCLUSION: This study demonstrated that the pituitary-adrenal response to oCRH in the elderly is gender specific and chronic stable disease (DM and HBP) is associated with altered regulation of the adrenal glucocorticoid response.

Sequential evaluation of islet cell responses to glucose in the transplanted pancreas in humans.

We evaluated the hormonal and metabolic responses of denervated pancreas allografts in nine volunteers 3 to 12 months after the transplant (initial) and again 1 year later (follow-up). Eight of the patients received simultaneous pancreas-kidney transplants. The glucose clamp technique was used to create a square wave of hyperglycemia 5.5 mmol/L above the basal glucose level for 2 hours. A biphasic insulin response was evident in each subject, both initially and at follow-up. The initial plasma insulin response was fourfold higher in patients with pancreas-kidney transplants than in normal volunteers. However, the plasma insulin response of the patients with pancreas-kidney transplants at the follow-up study was more similar to that of the normal controls. The plasma glucagon levels were elevated in follow-up clamp studies. Hepatic glucose production and glucose disposal were similar in both studies. At the follow-up examination only, GLUT4, the major insulin-sensitive glucose transporter, was measured in muscle homogenates by immunoblotting. GLUT4 levels in the patients with pancreas-kidney transplants were only 55% as abundant as in normal volunteers. This may be due, in part, to immunosuppressive therapy or to persistent, albeit reduced, levels of hyperinsulinemia even 2 years after transplantation. We concluded that, despite systemic drainage of the pancreas and immunosuppressive therapy, pancreatic insulin secretion, peripheral insulin levels, and muscle insulin responsiveness are restored toward normal levels approximately 2 years after the transplant.

Islet cell responses to glucose in human transplanted pancreas.

Postsurgery, pancreas transplantation results in alterations of carbohydrate metabolism. Additionally, immunosuppressive therapy impacts on glucose regulation. We evaluated the hormonal and metabolic responses of pancreas allografts, utilizing the hyperglycemic clamp technique coupled with the tritiated glucose methodology, in 11 volunteers who had received simultaneous pancreas-kidney transplantation (P-K) with systemic drainage. Their responses were compared with seven volunteers who had received only a kidney (K) graft and with seven normal control (C) volunteers. Although basal glucose and hepatic glucose output were similar in all three groups, basal insulin, C-peptide, glucagon, and pancreatic polypeptide were highest in the P-K group and lowest in normal subjects. During hyperglycemia, all groups showed a similar characteristic, initial complete suppression of hepatic glucose production, with recovery followed by a later suppression. Peripheral glucose uptake was similar in P-K and C subjects but decreased in K patients. Systemic insulin levels were fourfold higher in the pancreas transplant patients than in healthy subjects. Thus, under basal and hyperglycemic stimulation, 1) hepatic glucose homeostasis is regulated normally, even with pancreatic drainage into the systemic circulation; 2) overall glucose disposal is normal in P-K patients because of marked hyperinsulinemia; and 3) there is loss of tonic inhibition of endocrine pancreatic function secondary to pancreatic denervation.

Atrial natriuretic peptide suppresses osmostimulated vasopressin release in young and elderly humans.

Atrial natriuretic peptide (ANP) may suppress vasopressin release, but the dynamics of this interaction as well as the influence of age have not been defined. We studied six or seven young (19-40 yr old) and seven elderly volunteers (65-83 yr old) under two circumstances: 1) after infusion of 5% saline (0.04 ml.kg-1.min-1) for 2 h and 2) after the same infusion given with simultaneous synthetic human ANP (0.05 micrograms.kg-1.min-1). Hypertonic saline alone produced a progressive rise in plasma vasopressin with increasing serum sodium. During hypertonic saline alone, vasopressin levels began to rise at an increment in serum sodium of 1.67 +/- 0.35 mM in the young and 1.43 +/- 0.32 mM in the elderly and rose linearly with increasing serum sodium. When ANP was infused with hypertonic saline (with peak ANP levels of approximately 1,000 pM), vasopressin levels began to rise at an increment in serum sodium of 4.43 +/- 0.67 mM in the young and 4.57 +/- 0.43 mM in the elderly (P less than 0.01 vs. saline alone). Furthermore, the vasopressin response for any given serum sodium was significantly reduced in both young and elderly subjects, resulting in a rightward displacement of the curve relating vasopressin response to sodium concentration (P less than 0.001). In conclusion, ANP not only suppresses vasopressin but raises the threshold for release of vasopressin in response to osmotic stimulation in both young and elderly individuals. High circulating ANP levels may be responsible in part for the suppression of vasopressin levels and water diuresis seen during states of volume expansion.