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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral hyperinsulinaemia usually found in conventionally treated Type 1 (insulin-dependent) diabetic patients may have deleterious metabolic effects. We have used a hyperinsulinaemic model to examine intermediary metabolism in two key peripheral tissues, aorta and muscle. Nine pigs were immunized with crystalline insulin. Subsequently, they showed an insulin-binding capacity of 86.2 +/- 25.0 pmol/l and fasting total serum insulin of 3.9 +/- 3.1 nmol/l (control range 0.034-0.072 nmol/l), impaired glucose tolerance after oral glucose tolerance testing, significantly elevated levels of peripheral venous serum free insulin and C-peptide, and increased mean post-prandial free insulin/glucose ratios. The immunized pigs showed marked elevation of aorta and muscle triglycerides compared with control pigs (n = 15) but similar levels of non-esterified fatty acids. The glucose-6-phosphate-dehydrogenase, malic enzyme and 3-hydroxyacyl-CoA-dehydrogenase activities were all increased significantly (by 50%-300%) in both aorta and muscle. Phosphofructokinase was decreased in both tissues. Hexokinase was increased in muscle alone whereas pyruvate kinase was significantly decreased in aorta. Glyceraldehyde-3-phosphate dehydrogenase activity was not significantly different in aorta and muscle. Thus in insulin immunized pigs with normal beta-cell function and pronounced peripheral hyperinsulinaemia there was increased peripheral lipogenic activity. These findings have potentially important implications with regard to macrovascular disease in diabetes.
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PMID:Aorta and muscle metabolism in pigs with peripheral hyperinsulinaemia. 388 16

Peripheral hyperinsulinemia may be associated with metabolic consequences that could contribute to the high incidence of macrovascular disease in patients with diabetes mellitus. Arterial wall and striated muscle cells were studied in dogs to examine the effect of hyperinsulinemia on the lipid content and on lipogenic and glycolytic enzyme activity. Eight pancreatectomized dogs received segmental pancreatic autografts with venous drainage into the iliac vein. Glucose disappearance rates (K values) were normal four years after transplantation, but both fasting serum insulin levels (48.9 +/- 4.8 v 11.8 +/- 1.9 microU/mL) and the total area under the glucose-insulin response curve (1797 +/- 196 v 1110 +/- 158 microU X min/mL) were significantly greater than in control animals (P less than 0.05). The hyperinsulinemic dogs had a marked triglyceride elevation in arterial smooth muscle (20.6 +/- 8.0 v 0.5 +/- 0.4 mumol/g) and striated muscle (171.4 +/- 46.6 v 41.2 +/- 7.7 mumol/g) (P less than 0.001). Moreover, key enzymes in lipid synthesis (glucose-6-phosphate dehydrogenase, malic enzyme, and 3-hydroxyacyl-CoA DH) were significantly increased (P less than 0.01) in the hyperinsulinemic animals, while the glycolytic enzymes, (phosphofructokinase, hexokinase, pyruvate kinase, and alpha-glycerophosphate DH) were not significantly different. These data demonstrate substantial enhancement of lipid synthesis in arterial wall and striated muscle in hyperinsulinemic dogs. Altered substrate metabolism in arterial walls, in association with hyperinsulinemia, may have important implications with regard to macrovascular disease in diabetes, particularly in insulin-treated patients. In addition, these studies may serve to stimulate longer term assessments of macroangiopathy in the increasing number of patients with functioning pancreatic allografts draining into the systemic circulation.
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PMID:The effects of hyperinsulinemia on arterial wall and peripheral muscle metabolism in dogs. 390 54

Six men and three women with insulin-dependent diabetes (without complications) participated in physical training three times a week for 20 weeks. Physical training did not change the concentration of fasting blood-glucose, glucose excretion in urine or glucosylated haemoglobin (HbA1). However, the glucose disposal rate during euglycaemic clamp increased after training. In two patients a minor reduction of insulin dosage was necessary to alleviate slight hypoglycaemic episodes. The training resulted in significant increases in quadriceps isometric and dynamic strength and endurance. Maximal oxygen uptake increased by 8%, the activity of glycolytic enzymes in vastus lateralis muscle by 47% for hexokinase, and 30% for tri-osephosphate dehydrogenase and 25% for lactic dehydrogenase, the activity of oxidative enzymes by 42% for citrate synthase and 46% for 3-hydroxy-acyl-CoA-dehydrogenase. The glycogen concentration in the vastus lateralis muscle did not change significantly. Lipoprotein lipase activity did not change in muscle, nor in adipose tissue. The mean muscle fibre area increased by 25% and the area of FTa fibres by 30%. The new formation of capillaries around different muscle fibres was significant for FTb fibres (26%). The proliferation of capillaries, however, appeared to be insufficient to cope with the increased area of muscle fibres. As a result, the mean area of muscle fibre supplied by one capillary (a measure of diffusion distance) significantly increased after training for FTa fibres. It is concluded that with the exception of deficient proliferation of capillaries, patients with insulin-dependent diabetes mellitus show a normal central and peripheral adaptation to physical training. Physical training does not apparently improve blood glucose control in most cases, despite an increased insulin sensitivity.
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PMID:Muscle adaptations and glucose control after physical training in insulin-dependent diabetes mellitus. 394 85

The small intestine can utilize endogenous substrates for triglyceride synthesis. In diabetes mellitus, potential endogenous substrates are elevated. This study was designed to investigate whether intestinal triglyceride production utilizing endogenous substrates contributes to the pathogenesis of hyperlipidemia in diabetes. Intestinal fatty acid esterification as well as activities of acyl-CoA synthetase and acyl-CoA monoglyceride acyltransferase are the same in diabetic and control rats when the results are expressed per milligram protein. However, due to marked intestinal hypertrophy these activities are increased when the results are expressed as per centimeter gut length. In the mesenteric lymph fistula rat model, we found that during fasting diabetic rats have a greater than twofold increase in triglyceride output that is carried mainly by very low-density lipoproteins (VLDL). During lipid infusion, total triglyceride fatty acid output was not different between diabetic and control rats, although there were significant differences in the patterns of partition of endogenous and exogenous triglyceride into chylomicrons and VLDL. Endogenous triglyceride production did not increase in diabetic rats during lipid infusion. In contrast, there was a substantial increase in endogenous triglyceride production in the control group to a level comparable with that of the diabetic rats. There was a significant reduction in incorporation of exogenous triglyceride into chylomicrons in diabetic rats.
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PMID:Role of small intestine in pathogenesis of hyperlipidemia in diabetic rats. 402 44

The activities of beta-Hydroxy-beta-methylglutaryl CoA reductase (HMG CoA reductase), Acyl CoA: Cholesterol-O-acyltransferase (ACAT) and cholesterol 7 alpha-hydroxylase, the major enzymes involved in cholesterol metabolism, were determined in diabetic and non-diabetic rats after vagotomy and compared with those of sham-operated controls. Hepatic cholesterol levels and serum lipid profiles were also examined. In the non-diabetic animals vagotomy produced a significant increase in HMG CoA reductase (the rate limiting enzyme of cholesterol biosynthesis), and ACAT (the enzyme responsible for intracellular esterification) activities, while the activity of cholesterol 7 alpha-hydroxylase (which catalyses the rate determining step of bile acid biosynthesis) was significantly decreased. These rats had higher levels of free and esterified cholesterol in the liver and serum cholesterol levels were also increased in comparison with sham-operated animals. Vagotomized diabetic rats had similar HMG CoA reductase activity, but significantly reduced ACAT and reduced cholesterol 7 alpha-hydroxylase activity in comparison with sham-operated diabetic rats. There were significant alterations in hepatic and serum cholesterol fractions in both normal and diabetic rats after vagotomy. The results suggest that vagotomy leads to an increased rate of cholesterol synthesis and a decreased rate of cholesterol utilization, thus providing a possible mechanism for excessive cholesterol accumulation. These results are discussed in relation to alterations in cholesterol metabolism found in diabetic autonomic neuropathy.
Diabetes Res 1985 Nov
PMID:Cholesterol metabolism: regulatory effects of the vagus in the normal and diabetic animal. 407

1. The extractions of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo were calculated from measurements of their arterial and coronary sinus blood concentration. Elevation of plasma free fatty acid concentrations by infusion of intralipid and heparin resulted in increased extraction of free fatty acids and diminished extractions of glucose, lactate and pyruvate by the heart. It is suggested that metabolism of free fatty acids by the heart in vivo, as in vitro, may impair utilization of these substrates. These effects of elevated plasma free fatty acid concentrations on extractions by the heart in vivo were reversed by injection of dichloroacetate, which also improved extraction of lactate and pyruvate by the heart in vivo in alloxan diabetes. 2. Sodium dichloroacetate increased glucose oxidation and pyruvate oxidation in hearts from fed normal or alloxan-diabetic rats perfused with glucose and insulin. Dichloroacetate inhibited oxidation of acetate and 3-hydroxybutyrate and partially reversed inhibitory effects of these substrates on the oxidation of glucose. In rat diaphragm muscle dichloroacetate inhibited oxidation of acetate, 3-hydroxybutyrate and palmitate and increased glucose oxidation and pyruvate oxidation in diaphragms from alloxan-diabetic rats. Dichloroacetate increased the rate of glycolysis in hearts perfused with glucose, insulin and acetate and evidence is given that this results from a lowering of the citrate concentration within the cell, with a consequent activation of phosphofructokinase. 3. In hearts from normal rats perfused with glucose and insulin, dichloroacetate increased cell concentrations of acetyl-CoA, acetylcarnitine and glutamate and lowered those of aspartate and malate. In perfusions with glucose, insulin and acetate, dichloroacetate lowered the cell citrate concentration without lowering the acetyl-CoA or acetylcarnitine concentrations. Measurements of specific radioactivities of acetyl-CoA, acetylcarnitine and citrate in perfusions with [1-(14)C]acetate indicated that dichloroacetate lowered the specific radio-activity of these substrates in the perfused heart. Evidence is given that dichloroacetate may not be metabolized by the heart to dichloroacetyl-CoA or dichloroacetylcarnitine or citrate or CO(2). 4. We suggest that dichloroacetate may activate pyruvate dehydrogenase, thus increasing the oxidation of pyruvate to acetyl-CoA and acetylcarnitine and the conversion of acetyl-CoA into glutamate, with consumption of aspartate and malate. Possible mechanisms for the changes in cell citrate concentration and for inhibitory effects of dichloroacetate on the oxidation of acetate, 3-hydroxybutyrate and palmitate are discussed.
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PMID:Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo. 476 52

1. The total acid-soluble carnitine concentrations of four tissues from Merino sheep showed a wide variation not reported for other species. The concentrations were 134, 538, 3510 and 12900nmol/g wet wt. for liver, kidney cortex, heart and skeletal muscle (M. biceps femoris) respectively. 2. The concentration of acetyl-CoA was approximately equal to the concentration of free CoA in all four tissues and the concentration of acid-soluble CoA (free CoA plus acetyl-CoA) decreased in the order liver>kidney cortex>heart>skeletal muscle. 3. The total amount of acid-soluble carnitine in skeletal muscle of lambs was 40% of that in the adult sheep, whereas the concentration of acid-soluble CoA was 2.5 times as much. A similar inverse relationship between carnitine and CoA concentrations was observed when different muscles in the adult sheep were compared. 4. Carnitine was confined to the cytosol in all four tissues examined, whereas CoA was equally distributed between the mitochondria and cytosol in liver, approx. 25% was present in the cytosol in kidney cortex and virtually none in this fraction in heart and skeletal muscle. 5. Carnitine acetyltransferase (EC 2.3.1.7) was confined to the mitochondria in all four tissues and at least 90% of the activity was latent. 6. Acetate thiokinase (EC 6.2.1.1) was predominantly (90%) present in the cytosol in liver, but less than 10% was present in this fraction in heart and skeletal muscle. 7. In alloxan-diabetes, the concentration of acetylcarnitine was increased in all four tissues examined, but the total acid-soluble carnitine concentration was increased sevenfold in the liver and twofold in kidney cortex. 8. The concentration of acetyl-CoA was approximately equal to that of free CoA in the four tissues of the alloxan diabetic sheep, but the concentration of acid-soluble CoA in liver increased approximately twofold in alloxan-diabetes. 9. The relationship between CoA and carnitine and the role of carnitine acetyltransferase in the various tissues is discussed. The quantitative importance of carnitine in ruminant metabolism is also emphasized.
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PMID:Relationships between carnitine and coenzyme A esters in tissues of normal and alloxan-diabetic sheep. 507 38

1. The activities in rat tissues of 3-oxo acid CoA-transferase (the first enzyme involved in acetoacetate utilization) were found to be highest in kidney and heart. In submaxillary and adrenal glands the activities were about one-quarter of those in kidney and heart. In brain it was about one-tenth and was less in lung, spleen, skeletal muscle and epididymal fat. No activity was detectable in liver. 2. The activities of acetoacetyl-CoA thiolase were found roughly to parallel those of the transferase except for liver and adrenal glands. The high activity in the latter two tissues may be explained by additional roles of thiolase, namely, the production of acetyl-CoA from fatty acids. 3. The activities of the two enzymes in tissues of mouse, gerbil, golden hamster, guinea pig and sheep were similar to those of rat tissues. The notable exception was the low activity of the transferase and thiolase in sheep heart and brain. 4. The activities of the transferase in rat tissues did not change appreciably in starvation, alloxan-diabetes or on fat-feeding, where the rates of ketone-body utilization are increased. Thiolase activity increased in kidney and heart on fat-feeding. 5. The activity of 3-hydroxybutyrate dehydrogenase did not change in rat brain during starvation. 6. The factors controlling the rate of ketone-body utilization are discussed. It is concluded that the activities of the relevant enzymes in the adult rat do not control the variations in the rate of ketone-body utilization that occur in starvation or alloxan-diabetes. The controlling factor in these situations is the concentration of the ketone bodies in plasma and tissues.
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PMID:Activities of enzymes involved in acetoacetate utilization in adult mammalian tissues. 516 21

The effect of constant, controlled hyperinsulinemia on in vivo and in vitro insulin responsiveness has been investigated in rats that have received insulin infusions through chronically implanted jugular vein catheters. Constant rates of insulin infusion during days 1-4 resulted in stable plasma insulin concentrations. The plasma glucose initially fell from 122 +/- 3 to 53 +/- 4 mg/dl. While the infusion rate was maintained constant, the plasma glucose continued to fall over the subsequent days so that on day 4 the plasma glucose, 40 +/- 2 mg/dl, was significantly lower than that in the same animals on day 1 (P less than 0.02). Subsequently, the rate of insulin infusion was decreased to maintain the plasma glucose level in the 35-40 mg/dl range. Plasma catecholamine levels were high in insulin-infused rats. On the eighth day an in vivo insulin tolerance test (0.5 U/kg) was performed. Insulin-infused rats responded with a hypoglycemia that was both more pronounced and longer sustained than in saline-infused controls. Insulin responsiveness in vitro has been measured in isolated adipocytes. Adipocytes from epididymal fat pads were of similar size in the two groups of animals. Glucose uptake by adipocytes from insulin-infused rats was similar to that of controls under basal (zero insulin) conditions, but showed an increase in the maximum response to insulin. Glucose incorporation into total lipid and fatty acid was greater in adipocytes from insulin-infused rats than in controls under both basal (zero insulin) and insulin-stimulated conditions. Activities of the lipogenic enzymes acetyl CoA carboxylase and fatty acid synthetase were markedly increased in epididymal fat pads of insulin-infused rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1984 May
PMID:Increased insulin responsiveness in vivo and in vitro consequent to induced hyperinsulinemia in the rat. 614 6

Streptozotocin-induced diabetes significantly decreased rat liver microsomal long-chain fatty acyl-CoA (LCA-CoA) hydrolase. The decrease was observed using either palmitoyl-CoA (35 per cent, p less than 0.01) or oleoyl-CoA (23 per cent, p less than 0.01) as the substrate for the enzyme. Under the same conditions, diabetes did not significantly alter activity of LCA-CoA synthetase. Daily subcutaneous injections of protamine zinc insulin (10-12 units/day) into the diabetic rats returned their blood glucose to normal but only partially corrected the LCA-CoA hydrolase activity and did not effect LCA-CoA synthetase activity. The decreased LCA-CoA hydrolase and the unchanged LCA-CoA synthetase activities in the diabetic rat liver were interpreted as factors that may contribute to elevation of fatty acyl-CoA levels in the diabetic liver.
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PMID:Effects of streptozotocin-induced diabetes on microsomal long-chain fatty acyl-CoA synthetase and hydrolase. 614 82


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