The effect of hyperglycemia, hyperinsulinemia, and route of glucose administration on glucose oxidation and glucose storage

The separate effects of hyperinsulinemia, hyperglycemia, and the route of glucose administration on total glucose metabolism, glucose oxidation, and glucose storage were examined in 19 healthy young volunteers by employing the glucose clamp technique in combination with indirect calorimetry. Following 2 hr of euglycemic hyperinsulinemia (plasma insulin ～97μU/ml) created by intravenous insulin/glucose infusion, total glucose metabolism (6.08 ± 0.56 mg/kg. min), glucose oxidation ($\text{2.63 ± 0.26 mg}\text{0.26 mg kg · min}$), and glucose storage (3.46 ± 0.42 mg/kg · min) all increased 2 to 3-fold over basal rates. When additional hyperinsulinemia (163 ± 19 μU/ml) was created while maintaining euglycemia, total glucose metabolism (8.87 ± 0.69) and glucose storage (6.06 ± 0.51) both increased significantly (p < 0.005 and 0.02, respectively), but the rise in glucose oxidation (2.96 ± 0.17) was small and insignificant. During combined hyperglycemia (214 mg/dl) and hyperinsulinemia (217 μU/ml), total glucose metabolism (16.21 ± 0.58 mg/kg · min) and glucose storage (13.05 ± 0.57 mg/kg · min) both increased significantly (p < 0.001) compared to the euglycemic hyperinsulinemic conditions but glucose oxidation (3.04 ± 0.16 mg/kg · min) failed to increase further. These results indicate that the body's ability to oxidize glucose becomes saturated within the physiologic range of plasma insulin and glucose concentrations. With further increases in plasma glucose and insulin levels, the increase in glucose metabolism is primarily accounted for by an increase in glucose storage. The route of glucose administration, oral versus intravenous, had no effect on glucose oxidation. Under conditions of prolonged (6 hrs) euglycemic hyperinsulinemia, glucose oxidation was not significantly different whether the glucose was given intravenously (3.14 ± 0.11 mg/kg · min) or orally (3.63 ± 0.17). Similarly, under comparable conditios of hyperglycemic hyperinsulinemia, glucose oxidation was not different in subjects receiving intravenous (3.60 ± 0.28 mg/kg · min) and oral (4.03 ± 0.13) glucose. However, under conditions of hyperglycemic hyperinsulinemia both total body glucose metabolism (22.91 ± 0.42 versus 19.66 ± 1.10 mg/kg · min, p < 0.02) and glucose storage (18.76 ± 0.47 versus 15.95 ± 1.17, p < 0.02) were significantly greater during oral versus intravenous glucose. The site of the increased glucose storage observed with oral glucose could not be located since hepatic and femoral venous catheterization was not performed.     

Effect of long chain triglyceride infusion on glucose metabolism in man

The effect of long chain triglyceride infusions (Intralipid 20%, 1 ml/min) on total body glucose uptake, glucose oxidation and glucose storage was examined in 25 healthy young volunteers by employing the euglycemic insulin clamp technique in combination with indirect calorimetry. Insulin was infused at three different rates (0.5, 2 and 4 mU/kg min) to achieve steady state hyperinsulinemic plateaus of 60 ± 4, 170 ± 10 and 420 ± 15 μU/ml. Prior to Intralipid infusion, the mean basal plasma free fatty acid concentration of all subjects was 385 ± 8 μmole/l. Following 90 min Intralipid infusion, the mean plasma free fatty acid level was increased to 760 ± 20 μmole/l (p < 0.001). At each insulin dose level, hyperlipidemia caused a significant reduction in total glucose uptake (5.9–3.5, 9.9–7.1, 11.1–8.8 mg/kg min, all p < 0.001. The decrease in total body glucose uptake was reflected by a decrease in both total glucose oxidation (2.4–1.6, 3.4–2.2, 3.7–2.8 mg/kg min, all p < 0.001) and glucose storage (3.6–1.9, 6.5–4.9, 7.4–5.9 mg/kg min, all p < 0.001). Basal glucose oxidation (1.3 ± 0.1 mg/kg min) fell by about 30% following 90 min of Intralipid infusion (0.9 ± 0.1 mg/kg min). Six additional subjects were studied with a lower infusion rate of Intralipid (0.5 ml/min). In these studies, insulin was infused at two different doses (0.5 and 2 mU/kg min) to achieve steady state plasma levels of 62 ± 2 and 171 ± 4 μU/ml. Intralipid caused again a significant reduction in total body glucose uptake during both the low (5.9 to 4.5 mg/kg min, p < 0.001) and the high (9.9–8.7 mg/kg min, p < 0.01) insulin clamp studies. This decrease in total glucose uptake was again the combined effect of an inhibition of both glucose storate (p < 0.05) and glucose oxidation (p < 0.001). In both high and low dose Intralipid infusion protocols, a strong inverse correlation was noted between the plasma free fatty acid concentration during the insulin clamp study and total body glucose uptake (r = 0.92, p < 0.001), glucose oxidation (r = 0.95, p < 0.001), and glucose storage (r = 0.90, p < 0.01). These results indicate that the inhibitory effect of free fatty acids on glucose utilization involves the biochemical pathways regulating both glucose oxidation and glycogen synthesis.     

Endocrine abnormalities in patients undergoing long-term hemodialysis. The role of prolactin

The possible role of hyperprolactinemia in the sexual and thyroid abnormalities of patients with end-stage renal failure was studied in 56 patients undergoing long-term hemodialysis. Seventy-three per cent of the women and 25 per cent of the men receiving no prolactin (PRL)-enhancing drugs had elevated PRL levels (25 to 200 ng/ml, normal <20 ng/ml), and all those patients who were receiving α-methyldopa treatment (13 patients) had even higher PRL levels (30 to 1,107 ng/ml). The response of PRL to the administration of thyrotropin-releasing hormone (TRH) was blunted and prolonged, suggesting that hyperprolactinemia was in part due to prolonged plasma half-life of the hormones; this was confirmed by the insufficient PRL lowering effect of a single dose of bromocriptine in a short-term test, whereas a longer trial of six weeks demonstrated the PRL-suppressive effect of the drug.Amenorrhea or oligomenorrhea was a constant feature in women, four of whom also showed galactorrhea; during bromocriptine treatment, recurrence of menses was observed in some of the hyperprolactinemic amenorrheic women. Men with impotence had higher PRL levels than men with normal potency. Lack of appropriate elevation of luteinizing hormone (LH) levels despite low estradiol or testosterone levels was observed in approximately one third of the hyperprolactinemic subjects of both sexes, but also in a similar proportion of normoprolactinemic ones. However, treatment with bromocriptine resulted in an increase in basal LH in 13 of 16 patients with hyperprolactinemia. These data demonstrate that PRL measured in patients with advanced renal failure is biologically active and that hyperprolactinemia is one of the major factors in the hypogonadism of these patients. In addition, integrated circulating LH after the injection of exogenous luteinizing hormone-releasing hormone (LHRH) was normal, despite prolonged plasma half-life, suggesting that pituitary response was in fact impaired. Unrelated to PRL levels, 47 per cent of the patients had slightly elevated thyroid-stimulating hormone (TSH) levels, with normal total and free thyroxine (T4). Although triiodothyronine (T3) tended to cluster in the low-normal area, reverse-T3 levels were not consistent with preferential deiodination of T4 to reverse-T3. Elevation of the basal TSH levels was, at least in part, due to prolonged plasma half-life of the hormone. These biochemical changes were not related to clinically detectable dysfunction of the thyroid.     

Effect of a 3-day fast on glucose storage and oxidation in obese hyperinsulinemic diabetics

Glucose disposal was measured for a 3-hr period after a 100-g oral glucose load by means of a new adaptation of continuous indirect calorimetry in 6 obese hyperinsulinemic diabetics and 5 nonobese normal subjects who served as the control. While total glucose oxidized during the 3-hr test was not significantly lower in the obese diabetic group (31 ± 3 g) than in the control group (37 ± 3 g), a marked impairment of net glucose storage was observed in the former group (26 ± 7 g) in comparison to the control group (64 ± 3 g; p < 0.001). This marked decrease in net glucose storage suggests that a limited capacity for glucose storage might play a major role in glucose intolerance in these cases of obese hyperinsulinemic diabetes. In the obese diabetic group, after a 3-day fast supplemented with protein, the plasma glucose values dropped significantly both in the fasting state and in response to the glucose load. This was accompanied by a marked improvement of glucose storage (52 ± 9 versus 26 ± 7 g before the fast; p < 0.001), a decrease in glucose urinary loss (5 ± 1 g versus 14 ± 4 g prior to fast), but a marked impairment in glucose oxidation (13 ± 1 g versus 31 ± 3 g before fast; p < 0.001). In the control group, a moderate impairment of glucose tolerance was observed, probably related to the important decrease in glucose oxidation (12 ± 3 g versus 37 ± 3 g prior to fast), in spite of the increase in glucose storage (82 ± 4 g versus 64 ± 3 g prior to fast). These observations suggest that glucose intolerance observed in obese hyperinsulinemic diabetics in the postabsorptive state might result at least in part from deficiency in net glucose storage capacity. The marked lowering of the plasma glucose tolerance curve in the same subjects after a 3-day period of fast is probably a consequence of the overall effect of a decrease in the glucose pool and an increase in net glucose storage in spite of a decrease in glucose oxidation and in urinary glucose loss. It does not exclude, however, other factors, such as changes in tissue insulin sensitivity.     

Improvement of left ventricular function after percutaneous transluminal coronary angioplasty

Cardiac function and left ventricular dynamics were measured in seven consecutive patients 1 day before and 6 months after percutaneous transluminal balloon angioplasty of subtotal proximal stenosis of the left anterior descending coronary artery. Before angioplasty all patients had obvious left ventricular dysfunction during exercise and to a smaller degree during isoproterenol infusion; the condition of all patients was greatly improved 6 months after angioplasty. After angioplasty, left ventricular end-diastolic pressure was normal at rest and decreased from a mean (± standard error of the mean) of 33.8 ± 1.6 to 19.2 ± 0.5 mm Hg on exercise. Left ventricular ejection fraction, measured by a gated blood pooling technique with technetium-99m, improved on exercise from 46 ± 5.0 percent to 69 ± 1.0 percent. Cardiac output and stroke volume index increased significantly with exercise after angioplasty. The peak negative rate of pressure reduction in the left ventricle (dP/dt/min), an index of left ventricular relaxation, was highly abnormal on exercise before (2,307 ± 260 mm Hg/s) and increased to the normal range (3,154 ± 200 mm Hg/s) after angioplasty. The improvement in left ventricular function after transluminal angioplasty in these cases of proximal left anterior descending coronary arterial stenosis is extremely encouraging.     

Study on lipid metabolism in obesity diabetes

Knowing the relationship between obesity and diabetes, the purpose of our work was to study the alterations in lipid metabolism as measured by continuous indirect calorimetry in the course of a 100-g oral glucose-tolerance test in groups of obese patients without and with diabetes, respectively. Seventy-nine obese patients participated in the study. They were divided into four groups according to the degree of carbohydrate intolerance: group A, normal glucose tolerance; group B, impaired glucose tolerance; group C, diabetes with hyperinsulinemic response to the load; group D, diabetes with impaired insulin response. All four groups of patients presented an increase in lipid oxidation, both in the fasting state and during the three-hour glucose tolerance test, when compared to the control group. The lipid oxidation rate was roughly parallel to plasma free fatty acid (FFA) levels. The contribution of lipids to energy expenditure was higher in obese as compared to control subjects. These observations suggest that the larger part taken by lipids in the energy metabolism of both nondiabetic and diabetic obese humans is a consequence of their increased fat stores and that the resulting decrease in carbohydrate metabolism may lead, as a late consequence, to alterations in glucose tolerance. The latter may result in delayed glucose storage and oxidation in the obese patient.     

Comparison of glucose,fructose, sorbitol,and xylitol utilization in humans during insulin suppression

During fructose, sorbitol, and xylitol perfusions, carbohydrate utilization was studied by continuous indirect calorimetry and compared with glucose utilization during pharmacologic inhibition of endogenous insulin secretion. The experiment was performed in 28 normal volunteers divided into 5 groups (glucose, fructose, sorbitol, xylitol, and saline), each subject being its own control. Insulin suppression was obtained by means of a constant infusion of epinephrine (6 μg/min) and propranolol (0.08 mg/min). After 90 min, during plasma insulin steady state, each sugar or polyol was infused at a rate of 6 mg/kg/min for 120 min. In contrast with a rise in plasma glucose from 161 ± 6 mg/dl to 291 ± 14 mg/dl during glucose infusion, glucose levels remained unchanged during infusion of the glucose substitutes. Carbohydrate oxidation showed a rise of 24, 65, 76, and 44 mg/min during infusions of glucose, fructose, sorbitol, and xylitol, respectively. Lipid oxidation rates decreased by 7, 20, 33, and 23 mg/min during the same infusions. These results indicate that fructose, sorbitol, and xylitol are oxidized at a higher rate than glucose during suppression of endogenous insulin secretion, without any significant rise in glycemia.     

Comparative study of isomalt and sucrose by means of continuous indirect calorimetry

Isomalt (Palatinit) an equimolar mixture of alpha-D-glucopyranosido-1,6-sorbitol and alpha-D-glucopyranosido-1,6-mannitol, was compared to sucrose in a prospective double-blind controlled crossover study. The acute effects of oral ingestion of 30-g loads of isomalt or sucrose on plasma glucose, insulin, free fatty acids (FFA), lactic acid, and carbohydrate (CHO) and lipid oxidation were studied over six hours by means of continuous indirect calorimetry in ten healthy normal-weight subjects. Unlike sucrose, whose ingestion was followed by significant changes in plasma glucose, insulin, and lactic acid during the first 60 minutes of the test, no significant changes in these parameters were observed following the administration of isomalt. The increase in CHO oxidation occurring between 30 and 150 minutes was significantly lower (P less than 0.01) following isomalt than after sucrose. Conversely, the decrease in lipid oxidation was significantly less (P less than 0.01) after isomalt in comparison to sucrose. It is concluded that the rise in CHO oxidation and in plasma glucose and insulin levels is markedly reduced when sucrose is replaced by an equal weight of isomalt. In contrast to other sugar substitutes, no increase in plasma lactic acid was observed after isomalt administration.     

Blood amine acid levels in patients with insulin excess (functioning insulinoma) and insulin deficiency (diabetic ketosis).

Blood amino acid concentrations were determined in the postabsorptive state in nine patients with insulin excess (functioning insulinomas), nine juvenile-type diabetics with insulin deficiency (diabetic ketosis due to insulin withdrawal), six juvenile diabetics in moderate metabolic control, and five healthy control subjects. Blood branched-chain amino acid (BCAA) levels were elevated in diabetic ketosis and decreased in patients with insulinomas. Blood concentrations of BCAA were significantly correlated to blood glucose levels, and in diabetics they were also correlated to blood ketone bodies, serum free fatty acids, and glycerol levels. These data indicate an inverse relationship between circulating effective insulin levels and blood BCAA concentrations. It is suggested that blood levels of BCAA might represent an indicator of insulin-dependent alterations of protein metabolism.     

Comparison in normal volunteers of three converting enzyme inhibitors: RHC 3659, MK 421 and captopril

Three orally active angiotensin-converting enzyme inhibitors, captopril, MK 421 and RHC 3659, were compared in normal volunteers by evaluating their blocking effect on blood pressure response to exogenous angiotensin I. Whereas MK 421 has a slower onset of action and RHC 3659 seems less potent, the efficacy of the three drugs is comparable.     

Glycogen synthesis versus lipogenesis after a 500 gram carbohydrate meal in man

The respiratory exchange and urinary nitrogen excretion of 6 healthy male subjects (age 21 +/- 1 yr; body weight 70 +/- 2 kg; means +/- SD) were followed for 10 hr after ingestion of a large amount of carbohydrates (CHO) in the form of bread, jam, and fruit juice, equivalent to 479 g of starch. Peak values for blood glucose (6.6 +/- 0.6 mM; mean +/- SEM) and plasma insulin (139 +/- 26 microU/ml) were reached after 90 min at which time the nonprotein respiratory quotient (NP-RQ) had risen to 0.97. During the next 8 hr glucose levels remained near 5.5 mM while insulin declined gradually to 22 +/- 7 microU/ml. The average NP-RQ remained in the range of 0.91 to 0.98, though individual values exceeding 1.0 for very short periods were observed. The increase in energy expenditure above basal rates corresponded to a specific dynamic action (SDA) of 5.9 +/- 0.6%. Assuming the CHO load to be completely absorbed after 5 hr, and allowing for glucose oxidation calculated from the gas exchange data, the glycogen content of the subject's body tissue had then increased by 408 +/- 19 g. During the 10 hr after the meal, 133 g CHO, 17 g fat and 29 g protein were oxidized, providing respectively 66%, 19% and 15% of caloric expenditure, and leaving a gain in glycogen stores estimated at 346 +/- 12 g. The data imply that: (1) The capacity for glycogen storage in man in larger than generally believed, and (2) Fat synthesis from CHO will not exceed fat oxidation after one high-carbohydrate meal, even if it is uncommonly large. When a single high-carbohydrate meal is consumed, dietary CHO merely has the effect of reducing the rate of fat oxidation. These findings challenge the common perception that conversion of CHO to fat is an important pathway for the retention of dietary energy and for the accumulation of body fat.     

Distribution and metabolism of intravenously injected tritiated insulin in rats.

Semisynthetic [³H] insulin was used to follow the distribution and metabolism of intravenously injected insulin in rats. Chromatographic methods were used to separate intact labeled insulin from radioactive degradation products in the plasma, liver, kidneys, and skeletal muscle. The metabolic clearance rate of the injected insulin was 23.6 ± 1 ml/min/kg and the distribution space 85 ± 17 ml/kg for an injected dose of $\text{1.5 mU}\text{100}\text{g}$ body weight. The kidneys concentrated tritium relative to the plasma by up to ninefold; the liver also concentrated radioactivity, but to a lesser degree. Radioactive degradation products were found to be of either higher or lower molecular weight than insulin. The kidneys contained predominantly low-molecular-weight degradation products, accounting for 54% of the radioactivity in these organs even 5 min after injection. The liver, by contrast, contained predominantly high-molecular-weight degradation products. This material appeared in the liver before it was seen in the plasma, suggesting that the liver is responsible for its production. This suggestion was confirmed by analyzing plasma samples from rats injected intravenously with [³H] insulin following either functional hepatectomy or nephrectomy. The hepatectomized rats displayed less high-molecular-weight material in the plasma and 2–3 times more intact insulin when compared to controls. By contrast, nephrectomy resulted in no significant change in the percentage of either high- or low-molecular-weight degradation products in the plasma despite reduced insulin clearance. These data confirm the importance of the liver and kidneys in insulin metabolism. Since at least some of the high-molecular-weight-degradation products may be formed by reincorporation of [³H] phenylalanine (liberated by degradation of [³H] insulin) into newly synthesized protein, the importance of the liver in its production may be a reflection of the protein biosynthetic capacity of this organ.     

Oral glucose tolerance test: Effect of different glucose loads on splanchnic carbohydrate and substrate metabolism in healthy man

To evaluate the role of splanchnic metabolism in the disposal of orally ingested glucose and thereby to define the optimal glucose load for glucose tolerance testing, splanchnic glucose output (SGO), as determined by the hepatic-venous catheter technique, was estimated in 16 healthy male volunteers in the basal state and after different glucose loads. Following glucose ingestion of 12.5, 25, 50, 75, and 100 g glucose, mean SGO over 2 hours was 9, 10, 12.3, 20, and 24.7 g above basal hepatic glucose production or 72, 40, 25, 26, and 25 percent of the respective glucose load. Increasing glucose doses represented a greater and more prolonged insulinogenic stimulus as determined by insulin concentrations in hepatic venous plasma. Splanchnic lactate uptake decreased and finally reverted to a net output in most of the subjects studied, whereas pyruvate production increased with rising glucose loads. It is concluded that (1) maximal stimulation of insulin release by administration of 50 to 100 g glucose results in maximal splanchnic extraction (75%) of an ingested glucose load, whereas smaller amounts of glucose are retained to a lesser extent; (2) 100 g of glucose provide optimal conditions for performing an oral glucose tolerance test (OGTT), thereby provoking a relative as well as an absolute maximum of splanchnic glucose extraction; and (3) splanchnic uptake of pyruvate and lactate following ingestion of small amounts of glucose revert to a net output with utilization of increasing glucose loads.     

Beneficial effects of low-carbohydrate-high-protein diets in long-term diabetic rats

Groups of streptozotocin-diabetic rats (65 mg/kg subcutaneously) were fed ad lib. on three different diets over 12 mo: a low-carbohydrate (CHO)-high-protein (6%:63% of calories) diet; a moderate-CHO-high-protein (27%:50%) diet; and a standard control diet (68% as CHO, 20% as protein). The 6%-CHO diet resulted in an initial decrease in nonfasting blood glucose from 550 to 280 mg/dl, followed by a further gradual improvement ending with blood glucose levels below 160 mg/dl and reduction of glycosuria to physiologic amounts. In the group fed the 27%-CHO diet, there was a similar initial decrease in blood glucose, but blood glucose values below 160 mg/dl after 12 mo were attained in only 3 of 8 rats. All rats fed the standard 68%-CHO diet maintained blood glucose levels between 500 and 650 mg/dl throughout. The late recovery in the low-CHO fed groups was associated with increased pancreatic insulin content. Animals fed low-CHO diets showed a better weight gain and improved general condition. The onset of cataracts as observed with the hand slit-lamp was regularly delayed in the animals on the 6%- and 27%-CHO diet; in some instances, it was entirely prevented. The threshold concentration of blood glucose seemingly required for onset of cataracts was about 300 mg/dl. Nerve sorbitol and fructose levels were clearly higher in hyperglycemic animals and correlated well with the severity of hyperglycemia. Thus, low-CHO-high-protein diets, which markedly improve hyperglycemia, may also improve at least some of the secondary changes usually seen in severely hyperglycemic rats.     

Effects of the disaccharidase inhibitor acarbose on meal and intravenous glucose tolerance in normal man

To determine whether the effects of the disaccharidase inhibitor Acarbose on glucose tolerance could be solely explained via an action on intestinal nutrient absorption, the effects of this agent and placebo (100 mg p.o.) on intravenous and postprandial glucose tolerance were compared in six normal subjects. Acarbose significantly diminished plasma glucose, insulin, and gastrointestinal inhibitory polypeptide responses following meal ingestion without affecting plasma glucagon and pancreatic polypeptide responses, but had no effect on plasma glucose and insulin responses following intravenous injection of glucose. These results suggest that the acute effects of Acarbose on glucose tolerance can be explained on the basis of its ability to alter intestinal nutrient absorption.     

Distinct regulations by calcium of cyclic GMP levels and catecholamine secretion in isolated bovine adrenal chromaffin cells

The effects of various calcium-dependent secretagogues on cyclic GMP levels and catecholamine (CA) secretion were measured in a preparation of bovine adrenal chromaffin cells. The secretory effect of acetylcholine (ACh; 8--10 fold stimulation) was mimicked by nicotine but not muscarine. Three--five fold stimulations of cyclic GMP levels were also obtained with ACh and muscarine but not nicotine. High concentration of K+, and the ionophore A23187, also elevated cyclic GMP levels. However, secretion produced by veratridine, ouabain, and the ionophore X537A was not accompanied by any rise in cyclic GMP levels. Removal of extracellular calcium significantly decreased both basal levels of CA secretion and of cyclic GMP and completely abolished their stimulation by ACh. The half-maximal effects of calcium on the cholinergic stimulations of cyclic GMP levels and of CA secretion were observed at 0.2 and 2.5 mM, respectively. Substitution of Ca2+ by Sr2+ was more effective in maintaining the cyclic GMP response than the secretory response. The calcium channel blockers Co2+, Mg2+ and Ni2+ inhibited the cholinergic stimulation of cyclic GMP more than that of CA release. On the other hand, the organic calcium channel blockers, verapamil and methoxyverapamil (D--600) were more effective antagonists of the secretory response. These data indicate that the cholinergic stimulations of CA secretion and of cyclic GMP levels in bovine adrenal chromaffin cells are regulated by calcium via two distinct mechanisms.     

Fibrosing alveolitis and hepatitis B surface antigen-associated chronic active hepatitis in a patient with immunoglobulin A deficiency.

Fibrosing alveolitis is described in a 22 year old woman with immunoglobulin A (IgA) deficiency and hepatitis B surface antigen (HBsAg)-associated chronic active hepatitis. At lung biopsy HBsAg was detected by indirect immunofluorescence in the alveolar space but not in the septal fibrosis. We discuss the possible relationships between IgA deficiency on the one hand, and HBsAg-associated lung and liver diseases on the other hand.