Effect of medium- and long-chain triglyceride infusion on lipoprotein and hepatic lipase in healthy subjects

Plasma lipolytic activity and hydrolysis of intravenous fat were studied in six healthy subjects during infusion of a long-chain triglyceride (LCT) fat emulsion (Intralipid 20%) or of a medium-chain triglyceride (MCT)/LCT emulsion (Lipofundin MCT 20%). The fat emulsions were infused continuously at a rate of 0.17 g triglyceride kg-1 body weight (BW)h-1 for 6 h in random order at 7-day intervals. A continuous infusion of glucose (0.18 g kg-1 BW h-1) was administered for a period of 7 h and was started 1 h before the lipid infusion. Infusions of both types of fat increased plasma triglyceride (TG), free fatty acid (FFA) and lipoprotein lipase (LPL) levels and steady-state values were present during the 3rd to 5th h of infusion. MCT/LCT infusion resulted in higher plasma levels at steady-state of TG (3.63 +/- 0.45 [SEM] vs 2.73 +/- 0.45 mmol l-1; P less than 0.05), FFA (1.05 +/- 0.08 vs 0.54 +/- 0.04 mmol l-1; P less than 0.01) and LPL (4.6 +/- 0.6 vs 2.6 +/- 0.5 mU ml-1; P less than 0.05) in comparison with LCT administration. There was a positive correlation between plasma LPL activity and TG concentration (r = 0.77; P less than 0.001) when data for the two infusions were combined. Although the same amount of fat was infused on a weight basis, the molar infusion rate was 40% higher with MCT/LCT than with LCT infusion, due to differences in molecular weights (634 vs 885 Da).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin resistance in Graves'' disease: a quantitative in-vivo evaluation

Hyperthyroidism is considered to be an insulin-resistant state, but a quantitative evaluation of some action of insulin is still lacking. We performed euglycaemic clamp at about 350 and 7000 pmol l-1 plasma insulin concentration in combination with the 3H-glucose infusion in 12 patients with Graves' disease and in 12 matched controls. Fasting plasma insulin (126 +/- 6.5 vs. 77.5 +/- 5.7 pmol l-1; P less than 0.001), C-peptide (502 +/- 36 vs. 363 +/- 41 pmol l-1; P less than 0.001) and glucagon (47 +/- 3.3 vs. 33.3 +/- 3 pmol l-1; P less than 0.01) were significantly higher in hyperthyroids than in euthyroids. Basal hepatic glucose production was significantly higher in hyperthyroids than in euthyroids (18.3 +/- 1.4 vs. 9.2 +/- 0.5 mumol l-1; P less than 0.0001), and its suppression during physiological hyperinsulinaemia was only 50% in hyperthyroids. Glucose utilization and suppression of lipolysis were normally stimulated by insulin. All parameters altered during hyperthyroidism were normalized during methimazole-induced euthyroidism. We conclude that insulin resistance involves mainly glucose rather than lipid and is selective at the hepatic level.     

Decreased insulin secretory capacity and normal pancreatic B-cell glucose sensitivity in non-obese patients with NIDDM

We investigated the dose-response characteristics of glucose-induced insulin release and the influence of hyperglycaemia on arginine-induced insulin secretion in eight non-obese subjects with NIDDM and in eight non-diabetic volunteers. Plasma C-peptide levels, achieved during 60 min hyperglycaemic clamps with and without the infusion of a primed continuous infusion of arginine (infusion rate 15 mg kg-1 min-1) during the last 30 min, were analysed with a modified Michaelis-Menten equation. The insulin secretory capacity (Vmax) for glucose-stimulated insulin release showed a trend towards a negative correlation with the fasting blood glucose in the NIDDM subjects (r = 0.68, P = 0.6); it was lower than the Vmax of non-diabetic controls (2.2 +/- 0.2 vs 4.2 +/- 0.4 nmol l-1 respectively; P less than 0.001). The ED50 (half maximal stimulating blood glucose concentration) of the second-phase glucose-stimulated insulin release (determined from the plasma C-peptide levels at 60 min) was not significantly different from the ED50 of the controls (11.9 +/- 0.8 vs 13.3 +/- 1.9 mmol l-1 respectively; P greater than 0.2). Combined glucose-arginine stimulation significantly increased insulin release. The Vmax for both phases were significantly lower in NIDDM patients than in controls (2.3 +/- 0.2 vs 5.0 +/- 0.9 and 3.8 +/- 0.5 vs 8.5 +/- 0.9 nmol l-1 respectively; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man

Synthetic oxyntomodulin, a predicted product of the glucagon gene, which is produced in the human lower intestinal mucosa, was infused in doses of 100 and 400 ng kg-1 h-1 into six volunteers to study its pharmacokinetics and effects on pentagastrin-stimulated gastric acid secretion (100 ng kg-1 h-1). The concentration of oxyntomodulin in plasma measured with a cross-reacting glucagon assay increased from 37 +/- 5 to 106 +/- 17 and 301 +/- 40 pmol l-1, respectively. The metabolic clearance rate was 5.2 +/- 0.7 ml kg-1 min-1 and the half-life in plasma was 12 +/- 1 min. Oxyntomodulin reduced the pentagastrin-stimulated acid secretion by 20 +/- 9% during the low-rate infusion (P less than 0.05) and by 76 +/- 10% during the high-rate infusion (P less than 0.05). In accordance with the homology with glucagon, there was a small, significant rise in plasma concentrations of insulin and insulin C-peptide during oxyntomodulin infusion. Oxyntomodulin may therefore be included among the potential incretins and enterogastrones in man.     

Peripheral and hepatic insulin sensitivity in healthy elderly human subjects

Insulin resistance has been reported in normal ageing but discrepancies between such studies may be related to compounding factors such as body composition and exercise patterns. We employed a two-step hyperinsulinaemic euglycaemic clamp to assess peripheral and hepatic tissue insulin sensitivity and glucose recycling in 13 elderly (E) and 14 young (Y) healthy subjects controlling for the above factors. There was no difference in basal hepatic glucose production (E: 2.36 +/- 0.06, Y: 2.47 +/- 0.1 mg kg-1 min-1; P = 0.4). At step 1 (insulin infusion 15 mU kg-1 h-1) glucose turnover was similar (E: 2.65 +/- 0.13, Y: 2.88 +/- 0.22 mg kg-1 min-1; P = 0.4) but hepatic glucose production was lower in the elderly group (0.20 +/- 0.16 vs 0.64 +/- 0.10 mg kg-1 min-1; P = 0.03). At step 2 (insulin infusion 50 mU kg-1 h-1) glucose turnover was similar (E: 7.60 +/- 0.24, Y: 8.05 +/- 0.34 mg kg-1 min-1; P = 0.3) and hepatic glucose production was equal but negative (E: -1.35 +/- 0.18, Y: -1.34 +/- 0.22 mg kg-1 min-1; P = 0.9). Glucose recycling did not differ between the groups at any stage. Similar serum insulin levels were achieved in both groups at each step. Decreased glucose tolerance was confirmed in E with a higher 2 h blood glucose after an OGTT (5.3 +/- 0.4 vs 4.1 +/- 0.3 mmol l-1; P = 0.03) but incremental insulin response was similar (E: 3236 +/- 289, Y: 3586 +/- 463 mU l-1 min-1; P = 0.5). We conclude that changes in hepatic tissue insulin sensitivity do not cause the deterioration in glucose tolerance observed with age. A small reduction in both peripheral tissue insulin sensitivity and late insulin secretion may be responsible.     

Cholecystokinin is a physiological hormonal mediator of fat-induced inhibition of gastric emptying in man

The effect of cholecystokinin-33 on gastric emptying was studied in eight healthy men. The test meal was a firm custard pudding, labelled with 99mTc-Chelex-100 particles. Gastric emptying rate was measured, using a dual-headed gamma camera, and was expressed as the half time of the emptying curve. Plasma cholecystokinin concentrations were determined by radioimmunoassay. Subjects were studied three times: (i) during infusion of saline; during cholecystokinin infusion, (ii) 0.375 IDU kg-1 h-1 and (iii) 0.75 IDU kg-1 h-1. Furthermore, plasma cholecystokinin was determined after a regular meal. During saline, plasma cholecystokinin increased minimally. After the regular meal it increased from 1.6 to 6.5 pmol l-1 at 30 min, decreasing to 5.3 pmol l-1 at 60 min. During the lower and higher doses of cholecystokinin it increased from 1.0 and 1.4 to 4.5 and 7.3 pmol l-1, respectively. The lower and higher doses significantly (P less than 0.05) increased half emptying time, from 45 +/- 8 to 86 +/- 17 and 198 +/- 50 min, respectively. Cholecystokinin is most likely a physiological hormonal mediator of fat-induced inhibition of gastric emptying.     

The glucoregulatory and antilipolytic actions of insulin in abdominal obesity with normal or impaired glucose tolerance: an in vivo and in vitro study

To evaluate the effects of obesity and impaired glucose tolerance on insulin sensitivity, we performed a euglycaemic-hyperinsulinemic clamp at about 350 pmol l-1, combined with 3H-glucose infusion, in 14 obese patients, BMI 36.5 +/- 1.2 and in 12 matched controls, BMI 23.9 +/- 0.4. Six obese patients had normal glucose tolerance (oNGT), and eight had impaired glucose tolerance (oIGT). The ability of insulin to inhibit lipolysis in isolated adipocytes was also studied. Insulin-mediated glucose utilization was more severely impaired in oIGT than in oNGT with respect to the controls (621 +/- 51 vs. 897 +/- 83 vs. 1298 +/- 55 mumol m-2 min-1, P < 0.001). Plasma glycerol was higher in oIGT than in oNGT and in the controls, both fasting (238 +/- 12 vs. 179 +/- 14 vs. 112 +/- 8 mumol l-1, P < 0.001) and during the clamp (175 +/- 21 vs. 120 +/- 12 vs. 36 +/- 6 mumol l-1, P < 0.001). The correlation between glucose utilization and the percent reduction of plasma glycerol during the clamp was significant in the study group as a whole (r = 0.809, P = 0.0001), and in each of the groups separately (oIGT: r = 0.929, P = 0.002; oNGT: r = 0.943, P = 0.036; controls: r = 0.902, P = 0.0001). Inhibition by insulin of noradrenaline-stimulated lipolysis in isolated adipocytes was more severely impaired in oIGT than in oNGT compared with the controls (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of verapamil and converting enzyme inhibition on bilateral renal function of two-kidney, one-clip hypertensive rats

Experiments were conducted in two-kidney, one-clip renal vascular hypertensive rats (GHR) to assess the responses of each kidney to acute treatment with the antihypertensive calcium channel blocking agent verapamil in the presence and in the absence of converting enzyme inhibitor (CEI). One group of GHR (0.2 mm inner diam. clip 3 weeks before study) were examined during a control period, and during a second period of infusion of verapamil (600 micrograms h-1 kg-1). A second group of GHR were examined during a control period, during CEI (teprotide, 3 mg h-1 kg-1) infusion and during a third period of verapamil (600 micrograms h-1 kg-1) infusion superimposed on CEI infusion. Although systemic blood pressure (BP) decreased from 175 +/- 4 to 149 +/- 5 mmHg (mean +/- SEM) in response to verapamil alone, renal blood flow for non-clipped kidneys increased from 5.9 +/- 0.4 to 6.5 +/- 0.3 ml/min, indicating a 30% reduction of renal vascular resistance (P values less than or equal to 0.01; n = 9). Glomerular filtration rate (GFR) for non-clipped kidneys (n = 24) increased from 0.91 +/- 0.09 to 1.47 +/- 0.14 ml/min and filtration fraction increased from 0.32 +/- 0.04 to 0.47 +/- 0.03 (P values less than or equal to 0.05). Urine flow rate and absolute and fractional sodium excretion for non-clipped kidneys increased. GFR for clipped kidneys decreased during verapamil. Treatment with CEI alone resulted in nearly identical responses of BP and function of the non-clipped kidney, except filtration fraction was unchanged. The addition of verapamil to ongoing converting enzyme blockade tended to augment the increased GFR of the non-clipped kidney. Plasma renin activity (PRA) increased from 30 +/- 3 to 59 +/- 7 ng of angiotensin (ANG) I h-1 ml-1 with verapamil alone, a significantly larger increment than the increase of PRA from 27 +/- 5 to 39 +/- 9 ng of ANG I h-1 ml-1 in GHR subjected to comparable blood pressure reduction by mechanical aortic constriction. Verapamil resulted in many similar effects on renal function to those observed during blockade of converting enzyme. The increased filtration fraction observed in response to verapamil may be the result of vasodilatation of the afferent arteriole or of an increase in the glomerular ultrafiltration coefficient.     

Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.     

Effect of insulin on intracellular pH and phosphate metabolism in human skeletal muscle in vivo.

1. 31P nuclear magnetic resonance spectroscopy and the hyperinsulinaemic-euglycaemic clamp were used simultaneously to assess the effect of insulin on intracellular pH and the major phosphorus-containing metabolites of normal human skeletal muscle in vivo in four normal subjects. 2. Insulin and glucose were infused for 120 min. Plasma insulin increased approximately 10-fold over preclamp levels (5.6 +/- 0.9 m-units/l pre-clamp and 54 +/- 5 m-units/l over the last hour of infusion; mean +/- SEM, n = 4). Plasma glucose concentration did not change significantly (5.4 +/- 0.2 mmol/l pre-clamp and 5.5 +/- 0.1 mmol/l over the last hour of infusion). 3. Insulin and glucose infusion resulted in a decline in the intracellular pH of forearm muscle of 0.027 +/- 0.007 unit/h (P less than 0.01), whereas in control studies of the same subjects, pH rose by 0.046 +/- 0.005 unit/h (P less than 0.001). 4. In the clamp studies, intracellular inorganic phosphate concentration rose by 18%/h, whereas ATP, phosphocreatine and phosphomonoester concentrations did not change. In plasma, inorganic phosphate concentration was 1.16 +/- 0.05 mmol/l before infusion, and this decreased by a mean rate of 0.14 mmol h-1 l-1. No change was observed in any of these intracellular metabolites in the control studies. 5. The results show that, under physiological conditions, insulin does not raise intracellular pH in human muscle, and thus cannot influence muscle metabolism by this mechanism. The results also suggest that insulin causes a primary increase in the next flux of inorganic phosphate across the muscle cell membrane.     

The independent effect of ketone bodies on forearm glucose metabolism in normal man.

Ketone bodies and non-esterified fatty acids (NEFA) inhibit insulin stimulated glucose uptake in muscle in-vitro. In man the infusion of ketone bodies lowers plasma NEFA levels thus confounding the interpretation of individual effects. The aim of this study was to examine the effect of ketone bodies on insulin mediated forearm glucose metabolism independent of the changes in the plasma NEFA levels. Seven healthy men received sodium 3-hydroxybutyrate (15 mumol kg-1 min-1) or sodium bicarbonate (control) for 240 min. Heparin (0.2 U kg-1 min-1) and insulin (0.01 U kg-1 h-1) were infused for 90 min (pre-clamp), followed by insulin alone (0.025 U kg-1 h-1) and euglycaemia was maintained (clamp). Plasma NEFA levels and rates of forearm NEFA uptake (+23 +/- 14 and +49 +/- 21 [mean +/- SEM] nmol 100 ml forearm [FA]-1 min-1) were comparable during the pre-clamp periods, and were suppressed equally during hyperinsulinaemia. Sodium 3-hydroxybutyrate infusion raised the blood ketone body levels from 70 +/- 4 mumol/l to a plateau of 450 +/- 30 mumol/l, while control levels declined from baseline (ketone body vs control; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in plasma renin activity and haemodynamics during vasodilator therapy in conscious dogs with myocardial infarction or chronic volume overload

The aim of the study was to compare the changes in plasma renin activity induced by a vasodilator in normal dogs and in dogs with an impaired cardiac reserve. In normal conscious dogs, a 60-min nitroprusside infusion increased plasma renin activity from 1.05 +/- 0.26 to 8.35 +/- 1.20 ng, angiotensin I ml-1 h-1 (P less than 0.002) and heart rate from 83 +/- 6 to 149 +/- 15 beats/min (P less than 0.002). In five dogs in which a aortocaval fistula had been created 4 weeks earlier, the same infusion still increased plasma renin activity but significantly less than in normal dogs (0.90 +/- 0.29 to 4.44 +/- 0.64 ng ml-1 h-1; P less than 0.01) and the heart rate was unchanged (134 +/- 4 to 139 +/- 7 beats/min; NS). Similarly, in five dogs with a previous myocardial infarction, the heart rats response to nitroprusside was blunted (108 to 107 beats/min;NS) and plasma renin activity increased less than in normal dogs. Plasma renin activity also increased acutely after hydralazine administration in dogs which myocardial infarction (1.05 +/- 0.26 to 8.99 +/- 0.79 ng ml-1 h-1; P less than 0.05); after 1 week of hydralazine, plasma volume had increased from 54.9 +/- 0.9 ml kg-1 to 74.5 +/- 4.9 ml kg-1 (P less than 0.05) and plasma renin activity remained higher than control (4.66 +/- 0.66 ng ml-1 h-1; P less than 0.01). In conclusion, vasodilator therapy rapidly activates vasoconstrictor forces and fluid retention even in dogs with limited cardiac reserve. Although the regulation of plasma renin secretion appears altered in these models of heart disease, the renin response remains sufficient to seriously limit the beneficial effects of vasodilator therapy.     

Osmoregulation of thirst and vasopressin secretion in insulin-dependent diabetes mellitus

1. Osmotically stimulated thirst and vasopressin release were studied during infusions of hypertonic sodium chloride and hypertonic D-glucose in euglycaemic clamped diabetic patients and healthy controls. 2. Infusion of hypertonic sodium chloride caused similar elevations of plasma osmolality in diabetic patients (288.0 +/- 1.0 to 304.1 +/- 1.6 mosmol/kg, mean +/- SEM, P less than 0.001) and controls (288.6 +/- 0.9 to 305.7 +/- 0.6 mosmol/kg, P less than 0.001), accompanied by progressive increases in plasma vasopressin (diabetic patients, 0.9 +/- 0.3 to 7.7 +/- 1.5 pmol/l, P less than 0.001; controls 0.5 +/- 0.1 to 6.5 +/- 1.0 pmol/l, P less than 0.001) and thirst ratings (diabetic patients 1.0 +/- 0.2 to 7.1 +/- 0.5 cm, P less than 0.001; controls 1.8 +/- 0.4 to 8.0 +/- 0.5 cm, P less than 0.001) in both groups. 3. Drinking rapidly abolished thirst and vasopressin secretion before major changes in plasma osmolality occurred in both diabetic patients and healthy controls. 4. There were close and significant correlations between plasma vasopressin and plasma osmolality (diabetic patients, r = +0.89, controls r = +0.93) and between thirst and plasma osmolality (diabetic patients r = +0.95, controls r = +0.97) in both diabetic patients and healthy controls during hypertonic saline infusion. 5. Hypertonic D-glucose infusion caused similar elevations in blood glucose in diabetic patients (4.0 +/- 0.2 to 20.1 +/- 1.2 mmol/l, P less than 0.001) and healthy controls (4.3 +/- 0.1 to 19.3 +/- 1.2 mmol/l, P less than 0.001) but did not change plasma vasopressin or thirst ratings.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasoactive intestinal polypeptide stimulation of prolactin release and renin activity in normal man and patients with hyperprolactinaemia: effects of pretreatment with bromocriptine and dexamethazone

Vasoactive intestinal polypeptide (VIP) was infused into normal volunteers and patients with hyperprolactinaemia. Heart rate increased from 62 +/- 3 to 75 +/- 3 beats min-1 (P = 0.001) in controls and from 70 +/- 2 to 78 +/- 3 beats min-1 (P = 0.001) in hyperprolactinaemics. Similarly, haematocrit increased from 38 +/- 2 to 44 +/- 1% (P = 0.001) and from 40 +/- 1 to 43 +/- 2% (P = 0.002) and plasma renin activity from 910 +/- 59 to a peak of 3344 +/- 282 pg ml-1 h-1 (P = 0.001) and from 1577 +/- 671 to a peak of 4954 +/- 1364 pg ml-1 h-1 (P = 0.001) in the two groups, respectively. Prolactin concentrations rose in the control group only, from 134 +/- 11 to a peak of 377 +/- 35 mU 1(-1) (P = 0.001), whilst in the hyperprolactinaemics little change occurred from the pre-infusion concentration of 3873 +/- 2179 reaching a peak of 3998 +/- 2347 mU 1(-1) (P greater than 0.07). In separate studies, the normal subjects were pretreated with either bromocriptine or dexamethazone. Dexamethazone did not alter any parameter of the response to VIP. Bromocriptine did not affect the heart rate, haematocrit or renin response to VIP but clearly inhibited the rise in prolactin which remained at unmeasurable concentrations throughout the infusion.     

Youth type 2 diabetes: insulin resistance, beta-cell failure, or both?

OBJECTIVE: This study evaluates insulin sensitivity, pancreatic beta-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA(1c) to insulin sensitivity and BCF. RESEARCH DESIGN AND METHODS: The subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU . m(-2) . min(-1)) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-(2)H(2)]glucose. RESULTS: Fasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 +/- 1.1 vs. 12.3 +/- 0.5 micromol . kg(-1) . min(-1); P = 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 +/- 0.1 vs. 2.0 +/- 0.2 micromol . kg(-1) . min(-1) per pmol/l; P = 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 +/- 24.6 vs. 220.2 +/- 18.0 pmol/l; P = 0.007), and FPIS and SPIS were lower (FPIS: 357.6 +/- 42.0 vs. 1,365.0 +/- 111.0 pmol/l; SPIS: 652.2 +/- 88.8 vs. 1,376.4 +/- 88.8 pmol/l; P < 0.001 for both). The glucose disposition index (GDI = insulin sensitivity x FPIS) was approximately 86% lower in type 2 diabetic patients than in obese control subjects. HbA(1c) correlated with FPIS (r = -0.61, P = 0.025) with no relationship to insulin sensitivity. CONCLUSIONS: Despite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA(1c) may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of beta-cell failure and means of retarding and/or preventing it.     

Comparison of metabolic effects of white beans processed into two different physical forms

In the present study eight control subjects and eight patients with non-insulin-dependent diabetes mellitus (NIDDM) consumed single portions of processed beans equivalent to 50 g of carbohydrate. The beans were processed by different methods into two physical forms; one maintained the integrity of the bean cells (undamaged bean cells, UC) and the other ruptured the bean cells (damaged bean cells, DC). Incremental glucose response areas after ingestion of either UC or DC were not significantly different in control subjects, while incremental insulin response areas (49 +/- 7 vs. 26 +/- 4 microU X ml-1 X h-1, P less than .05) were significantly lower after eating UC-processed beans. In patients with NIDDM both incremental glucose (150 +/- 14 vs. 73 +/- 25 mg X dl-1 X h-1, P less than .001) and insulin (67 +/- 16 vs. 46 +/- 11 microU X ml-1 X h-1, P less than .05) response areas were significantly lower after UC administration. To test the effectiveness of the UC-processed bean when incorporated into mixed meals, nine patients with NIDDM consumed mixed meals containing either DC or UC on two separate mornings. The test meals represented a typical Mexican American use of pureed beans wrapped in a flour tortilla topped with melted cheese. Incremental glucose responses were significantly lower after the UC meal (171 +/- 42 mg X dl-1 X h-1, P less than .05) when compared with the DC meal (212 +/- 34 mg X dl-1 X h-1). Incremental insulin areas were also lower after the UC (91 +/- 19 microU X ml-1 X h-1) when compared with the DC meal (120 +/- 22 microU X ml-1 X h-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased hepatic efficacy of urea synthesis from alanine in insulin-dependent diabetes mellitus

The relation of urea synthesis rate to blood alanine concentration was assessed in seven healthy controls and in 18 patients with insulin-dependent diabetes mellitus (HbAlc = 8.4 +/- 1.0% (mean +/- SD)). Following an overnight fast alanine was infused at 2 mmol h-1 kg-1 body weight. The hourly rate of urea synthesis was determined as the urinary excretion of urea corrected for accumulation of urea in total body water and intestinal hydrolysis. The functional hepatic nitrogen clearance, i.e. the relation of urea synthesis rate to blood alanine concentration, was calculated as the slope of linear regression of urea synthesis rates on blood alanine concentrations. Fasting glucagon concentrations were 85 +/- 26 ng l-1 in controls and 161 +/- 35 ng l-1 (P less than 0.01) in patients. The functional hepatic nitrogen clearances were 21.8 +/- 4.4 l h-1 in controls and 44.7 +/- 12.4 l h-1 (P less than 0.001) in patients. By multiple step-wise linear regression analysis the functional hepatic nitrogen clearance was found to correlate independently to fasting glucagon concentration, duration of diabetes, change in blood glucose and insulin following alanine infusion (r2 = 0.74). In a simple linear regression analysis the functional hepatic nitrogen clearance correlated strongly to fasting glucagon concentration (r2 = 0.54). In conclusion the kinetics of urea synthesis in insulin-dependent diabetes is changed in favour of increased conversion of alanine-N to urea-N at any blood amino acid concentration. The increased FHNC correlates strongly with hyperglucagonaemia.     

Renal excretion of prostaglandin E2 and plasma renin activity in type I diabetes mellitus: relationship to normoglycemia achieved with artificial pancreas

To determine the effect of normoglycemia on renal prostaglandin synthesis and renin-angiotensin system activity, prostaglandin E2 (PGE2) urinary excretion, plasma renin activity (PRA), and glomerular filtration rate (GFR) were studied in seven patients with insulin-dependent diabetes mellitus (IDDM) without complications, both in basal conditions and after a 20-h treatment with an artificial pancreas. Normoglycemia induced a significant reduction in PGE2 excretion (88 +/- 23 vs. 55 +/- 25 ng/12 h, P less than .05) and GFR (138 +/- 34 vs. 105 +/- 20 ml X min-1 X 1.73 m-2, P less than .05) and a nonsignificant increment of PRA (0.52 +/- 0.48 vs. 0.83 +/- 0.92 ng X ml-1 X h-1). The results enhance the hypothesis that renal prostaglandins play a role in the renal functional alterations observed in IDDM during hyperglycemia.     

Very low density lipoprotein metabolism after insulin over-treatment and during a euglycaemic clamp

The disturbance of very low density lipoprotein (VLDL) metabolism that occurs as a result of intensive insulin treatment and during a euglycaemic clamp have been investigated in a rat model. Normal rats were maintained with fed blood glucose levels below 5 mmol l-1 for 8 weeks by subcutaneous insulin injections (normal fed levels 5.8 +/- 0.4 (SD) mmol l-1). Glucose requirement to maintain a glucose clamp was significantly reduced (116 +/- 3 mumol min-1 kg-1 (SE) vs. 173 +/- 5 mumol min-1 kg-1, P less than 0.001), compared with weight-matched normal control rats. In the fasting state (blood glucose 3.5 +/- 0.2 mmol l-1 vs. 3.9 +/- 0.1 mmol l-1, NS) plasma non-esterified fatty acid levels were reduced. Fasting VLDL-triglyceride turnover, measured by bolus injection of 14C-VLDL, was also lower (3.17 +/- 0.12 mumol min-1 kg-1 vs. 3.50 +/- 0.07 mumol min-1 kg-1, P less than 0.05). Despite decreased turnover, insulin over-treated rats had normal plasma triglyceride concentrations indicating a removal defect. At the end of a 3-h euglycaemic clamp, plasma triglyceride concentrations and VLDL-triglyceride turnover were decreased in both normal control and insulin over-treated animals, and turnover remained significantly lower in the insulin over-treated rats (2.59 +/- 0.13 mumol min-1 kg-1 vs. 3.08 +/- 0.10 mumol min-1 kg-1, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of insulin on the rise in blood pressure and plasma aldosterone after angiotensin II in normal man

1. The effect of an intravenous infusion of insulin [2.5 units h-1 (m2 of body surface area)-1] on the rise in blood pressure and plasma aldosterone after intravenous angiotensin II (5, 10, and 20 ng min-1 kg-1) was investigated in six healthy, sodium-loaded men. 2. Serum insulin reached 96.8 +/- 18.1 mu-units/ml (control: 7.0 +/- 1.5 mu-units/ml) and serum potassium fell from 4.2 +/- 0.2 mmol/l to 3.6 +/- 0.2 mmol/l (P less than 0.005). 3. Hyperinsulinaemia increased (P less than 0.05) the secretion of aldosterone during the largest dose of angiotensin II (20 ng min-1 kg-1), but had no effect on the rise in blood pressure after angiotensin II.