[Diabetes and diet--changes in insulin resistance induced by food and need of individualized dietary guidelines].
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Diabetes Mellitus↗
Biomedical subjects
O Pedersen
Publications and source records attributed to O Pedersen.
[Insulin resistance--a physiopathological condition with numerous sequelae: non-insulin-dependent diabetes mellitus (NIDDM), android obesity, essential hypertension, dyslipidemia and atherosclerosis].
Recent research has demonstrated that reduced insulin-stimulated glucose metabolism in skeletal muscle (insulin resistance) and hyperinsulinism are common features in widespread diseases such as essential hypertension, android obesity, non-insulin dependent diabetes mellitus, dyslipidemia (in the form of raised serum triglyceride and reduced serum high-density lipoprotein (HDL) cholesterol) and arteriosclerosis. Simultaneously, investigations in a comprehensive group of healthy middle-aged men have revealed insulin resistance in one fourth. On the basis of these observations, a working hypothesis is suggested which postulates that genetic abnormalities in one or more of the candidate genes in the modes of action of insulin occur in a great proportion of the population. These may result in insulin resistance (primary genetic insulin resistance). Primary insulin resistance may be potentiated by a series of circumstances such as ageing, high-fat diet, lack of physical activity, hormonal and metabolic abnormalities or drugs (secondary insulin resistance). As a consequence of the reduced effect of insulin on muscle tissue, compensatory hyperinsulinism develops. Depending on the remaining vulnerability of the individual the hyperinsulinism is presumed to result in development of one or more phenotypes. For example if the beta-cells of the pancreas are unable to secrete sufficient insulin to compensate the insulin resistance on account of genetic defects, glucose intolerance will develop. In a similar manner, hyperinsulinism in insulin-resistant individuals who are predisposed to essential hypertension is presumed to reveal genetic defects in the blood pressure regulating mechanisms and thus contribute to development of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of perindopril on insulin sensitivity and plasma lipid profile in hypertensive non-insulin-dependent diabetic patients.
About 40% of patients with non-insulin-dependent diabetes (NIDDM) have hypertension, which in turn may contribute to their enhanced risk for cardiovascular diseases. However, a number of antihypertensive agents tend to cause a deterioration in the control of diabetes. The present study was designed to elucidate whether treatment with perindopril (a new angiotensin-converting enzyme [ACE] inhibitor) affects plasma lipid metabolism, glucose homeostasis, and insulin sensitivity. Ten patients with NIDDM and moderate hypertension were studied in a double-blind, placebo-controlled, crossover study encompassing 6 weeks of placebo treatment and 6 weeks of perindopril treatment given in random order. Mean systolic/diastolic blood pressure was 162/94 +/- 6/3 mm Hg during placebo treatment versus 157/91 +/- 5/2 mm Hg during perindopril therapy. Plasma levels of free fatty acids, triglycerides, high density lipoprotein (HDL) cholesterol, and total cholesterol were similar during placebo and perindopril treatment. Oral glucose tolerance tests showed similar responses of plasma glucose, serum insulin, and serum C peptide following placebo and perindopril treatment. Insulin sensitivity estimated with an intravenous insulin tolerance test (IVITT) was unchanged by perindopril therapy (KIVITT: 0.014 +/- 0.001 min-1 [placebo] versus 0.015 +/- 0.003 min-1 [perindopril], difference not significant. In conclusion, treatment with perindopril in NIDDM patients had no adverse effects on plasma lipids, glucose tolerance, or insulin sensitivity.
Aged↗
[Dietary treatment of diabetes mellitus. Background and rationale for recommendations in the 1990's].
Individual dietary regulation is still an important part of all forms of treatment of diabetes. In insulin dependent diabetes (IDDM) it is rational to advise the patient 1) to arrange his diet so that this results in a low glycaemic response, which implies a relatively high intake of dietary fibre and polysaccharides, 2) to distribute the food into 5-6 daily meals and 3) to consume a low-fat diet. This prevents too pronounced postprandial hyperglycaemia and hypoglycaemia between meals. Simultaneously, insulin sensitivity is increased and not only the insulin requirement but also peripheral hyperinsulinism tend to be reduced. Dietary regulation in IDDM is thus a compensation for the defective synchronization of variations in the plasma levels of glucose and insulin in the present day forms of insulin therapy. Nine out of ten diabetic patients are non-insulin dependent (NIDDM). The great majority are obese, 50% have essential hypertension and just as many have dyslipidaemia (raised serum triglyceride and reduced serum high density lipoprotein (HDL)-cholesterol). The condition is characterized pathophysiologically by insulin resistance in muscle, fat and liver tissue and delayed and frequently reduced glucose-stimulated secretion of insulin. The most important element in dietary regulation in NIDDM is, therefore, reduction of the energy content of the food with the object of achieving and maintaining reduction in weight. Even moderate reduction, in the majority of NIDDM patients, will have the effect that metabolism of carbohydrates and lipids becomes approximately normal on account of considerable increase in insulin sensitivity and to a lesser degree increased secretion of insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
[Recommendations for diabetic diet].
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Diet, Diabetic↗
In vivo insulin action and muscle glycogen synthase activity in type 2 (non-insulin-dependent) diabetes mellitus: effects of diet treatment.
Insulin resistant glucose metabolism is a key element in the pathogenesis of Type 2 (non-insulin-dependent) diabetes mellitus. Insulin resistance may be of both primary (genetic) and secondary (metabolic) origin. Before and after diet-induced improvement of glycaemic control seven obese patients with newly-diagnosed Type 2 diabetes were studied with the euglycaemic clamp technique in combination with indirect calorimetry and forearm glucose balance. Muscle biopsies were obtained in the basal state and again after 3 h of hyperinsulinaemia (200 mU/l) for studies of insulin receptor and glycogen synthase activities. Similar studies were performed in seven matched control subjects. Insulin-stimulated glucose utilization improved from 110 +/- 11 to 183 +/- 23 mg.m-2.min-1 (p less than 0.03); control subjects: 219 +/- 23 mg.m-2.min-1 (p = NS, vs post-diet Type 2 diabetes). Non-oxidative glucose disposal increased from 74 +/- 17 to 138 +/- 19 mg.m-2.min-1 (p less than 0.03), control subjects: 159 +/- 22 mg.m-2.min-1 (p = NS, vs post-diet Type 2 diabetic patients). Forearm blood glucose uptake during hyperinsulinaemia increased from 1.58 +/- 0.54 to 3.35 +/- 0.23 mumol.l-1.min-1 (p less than 0.05), control subjects: 2.99 +/- 0.86 mumol.l-1.min-1 (p = NS, vs post-diet Type 2 diabetes). After diet therapy the increase in insulin sensitivity correlated with reductions in fasting plasma glucose levels (r = 0.97, p less than 0.001), reductions in serum fructosamine (r = 0.77, p less than 0.05), and weight loss (r = 0.78, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Different approaches for estimating the deposition of radiocaesium on mountain pasture in southern Norway.
Different approaches to the estimation of radiocaesium deposition on different types of indigenous mountain pastures have been examined. In situ gamma spectrometric measurements performed using a portable multi-channel analyser (3 x 3 in Nal detector) with the detector placed on the ground, on a tripod at a height of 100 cm above the ground or fastened to a rucksack frame 90 cm above the ground were compared with conventional soil sampling. Field gamma-ray measurements in connection with soil sampling appear to be a promising tool for estimates of deposition on mineral soils in areas with different topography and vegetation.
Accidents↗
Divergent regulation of the Glut 1 and Glut 4 glucose transporters in isolated adipocytes from Zucker rats.
We have studied the relationship between glucose uptake rate and Glut 1 and Glut 4 protein and mRNA levels per fat cell in lean (FA/FA) and obese (fa/fa) Zucker rats at 5, 10, and 20 wk of age, and after induction of acute diabetes with streptozotocin. 5 wk obese rats exhibit insulin hyperresponsive glucose uptake, whereas 20 wk obese rats show insulin resistant glucose uptake. The relative abundance of Glut 1 and Glut 4 mRNA and protein per equal amount of total RNA and total membrane protein, respectively, is lower in adipocytes from obese rats. However, at all ages the enlargement of fat cells from obese rats is accompanied by a severalfold increase in total RNA and total membrane protein per cell. Thus, on a cellular basis, mRNA and protein levels of Glut 4 increases in young obese rats and gradually declines as a function of age. Basal glucose uptake is increased severalfold in fat cells from obese rats, and in parallel Glut 1 expression per cell in obese rats is two- to threefold increased over lean rats at all ages. Acute diabetes in 20 wk obese rats causes a profound downregulation of glucose uptake and a concomitant reduction of both Glut 1 and Glut 4 protein levels. Thus, changes in Glut 4 expression are a major cause of alteration in insulin-stimulated glucose uptake of adipocytes during evolution of obesity and diabetes in Zucker rats.
Adipose Tissue↗
Expression of GLUT1 and GLUT4 glucose transporters in skeletal muscle of humans with insulin-dependent diabetes mellitus: regulatory effects of metabolic factors.
Insulin-dependent diabetes mellitus (IDDM) is associated with insulin deficiency and insulin-resistant glucose uptake in skeletal muscle. To investigate the molecular mechanisms for this insulin resistance, we examined the expression of GLUT1 and GLUT4, glucose transporter genes in vastus lateralis muscle from 20 IDDM subjects and 10 nondiabetic controls. Both groups had a mean age of 34 yr and were nonobese. Fasting free plasma insulin levels were similar in control and IDDM subjects but hemoglobin A1c (HbA1c), fasting plasma glucose and free fatty acid levels were significantly higher in IDDM subjects. Euglycemic clamp studies over a range of insulin concentrations in these IDDM subjects previously showed both decreased insulin sensitivity and decreased maximally insulin stimulated glucose utilization. In this study, Northern blotting of muscle ribonucleic acid (RNA) revealed a single 3.0-3.5 kb transcript for both GLUT1 and GLUT4 with no change in messenger RNA (mRNA) size or abundance with IDDM. In IDDM subjects, GLUT1 mRNA levels correlated positively with HbA1c whereas GLUT4 mRNA levels correlated negatively with fasting plasma glucose but not with HbA1c. Neither mRNA correlated with fasting plasma insulin or free fatty acid levels or with daily insulin dose. Immunoblotting of total muscle membranes for GLUT4 showed a single band of mol mass of approximately 45 kilodaltons with no change in size or abundance with IDDM. There was no significant correlation between GLUT4 polypeptide levels and HbA1c, fasting plasma glucose, insulin, or free fatty acids, daily insulin dose, duration of diabetes, or subject age but in IDDM subjects GLUT4 protein levels correlated negatively with body mass index. Thus, impaired expression of glucose transporters in muscle is not essential for the pathogenesis of insulin-resistant glucose uptake in IDDM. No direct regulatory role of chronic glycemic control or plasma insulin levels on GLUT4 expression is evident. In contrast, recent ambient glucose levels may affect levels of GLUT4 mRNA but not GLUT4 protein, suggesting important posttranscriptional regulation of this protein. Since glucose transport has been shown to be rate limiting for glucose utilization in muscle in IDDM, these results suggest impaired translocation or activation of glucose transporters in IDDM.
Actins↗
Tissue-specific regulation of glucose transporters in different forms of obesity.
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Adipose Tissue↗
Effects of sulfonylureas on adipocyte and skeletal muscle insulin action in patients with non-insulin-dependent diabetes mellitus.
The effect of glibenclamide treatment on insulin action in isolated fat cells was studied in eight moderately obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin receptor binding and the effect of insulin on glucose transport and lipogenesis were determined before and after 3 months of glibenclamide therapy. At the end of the treatment period, mean daytime plasma glucose concentrations were reduced (10.8 +/- 0.4 versus 7.0 +/- 0.3 mmol/L, p less than 0.001) whereas mean daytime plasma insulin level was increased (40 +/- 12 versus 71 +/- 9 mU/L, p less than 0.001). Adipocyte insulin receptor binding as well as basal glucose transport and metabolism were unaffected by drug treatment. In contrast, insulin-stimulated glucose transport and lipogenesis were both significantly enhanced (p less than 0.05). These findings are comparable to those of another study involving seven moderately obese subjects with NIDDM who had biopsies of the lateral vastus muscle taken for measurement of insulin receptor function and glycogen synthase activity before and during 2 months of gliclazide treatment. In that study insulin receptors purified with wheatgerm agglutinin showed unchanged insulin binding and receptor kinase activity. Moreover, gliclazide had no impact on maximal glycogen synthase activity. However, under physiologic hyperinsulinemic conditions gliclazide therapy was associated with an increased sensitivity of glycogen synthase for its allosteric activation by glucose-6-phosphatase (p less than 0.04). In conclusion, sulfonylurea treatment of NIDDM enhances insulin-stimulated peripheral glucose utilization in part through a potentiation of insulin action on adipose tissue glucose transport and lipogenesis and skeletal muscle glycogen synthase.
Adipose Tissue↗
Decreased hepatic glucagon responses in type 1 (insulin-dependent) diabetes mellitus.
The effect of glucagon infusion on hepatic glucose production during euglycaemia was evaluated in seven Type 1 (insulin-dependent) diabetic patients and in ten control subjects. In the diabetic subjects normoglycaemia was maintained during the night preceding the study by a variable intravenous insulin and glucose infusion. During the study endogenous insulin secretion was suppressed by somatostatin (450 micrograms/h) and replaced by insulin infusion (0.15 mU.kg-1.min-1). 3H-glucose was infused for isotopic determination of glucose turnover. Plasma glucose was clamped at 5 mmol/l for 2 h 30 min and glucagon (1.5 ng.kg-1.min-1) was then infused for the following 3 h. Hepatic glucose production and glucose utilisation were measured during the first, second and third hour of the glucagon infusion. Basal hepatic glucose production (just prior to glucagon infusion) was similar in diabetic (1.2 +/- 0.3 mg.kg-1.min-1) and control (1.6 +/- 0.1 mg.kg-1.min-1) subjects. In diabetic patients hepatic glucose production rose slowly to 2.1 +/- 0.5 mg.kg-1.min-1 during the first hours of glucagon infusion and stabilized at this level (2.4 +/- 0.5 mg.kg-1.min-1) in the third hour. In control subjects hepatic glucose production increased sharply to higher levels than in the diabetic subjects (3.4 +/- 0.3 mg.kg-1.min-1) during the first and second hour of glucagon infusion (p less than 0.05) and then gradually fell (2.9 +/- 0.4 mg.kg-1.min-1) during the third hour. In conclusion, when stimulated with glucagon at a physiologic plasma concentration diabetic patients had 1) an overall reduced hepatic glucose production response and 2) an abnormal sluggish response pattern.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Hydroxybutyric Acid↗
Effects of hyperinsulinemia and hyperglycemia on insulin receptor function and glycogen synthase activation in skeletal muscle of normal man.
Insulin receptor function, glycogen synthase activity, and activation by phosphatases were studied in biopsies of human skeletal muscle under conditions of hyperglycemia and/or hyperinsulinemia for 150 minutes. Twenty-one healthy volunteers underwent either (A) a hyperinsulinemic, euglycemic clamp (serum insulin, 160.0 +/- 7.7 mU/L; plasma glucose, 4.9 +/- 0.1 mmol/L; n = 9), (B) a hyperglycemic clamp during normoinsulinemia (serum insulin, 18.1 +/- 3.3 mU/L; plasma glucose, 12.9 +/- 0.2 mmol/L; n = 6), or (C) a combined hyperinsulinemic, hyperglycemic clamp (serum insulin, 158.3 +/- 15.0 mU/L; plasma glucose, 11.4 +/- 0.8 mmol/L; n = 6). During all studies, the endogenous insulin secretion was inhibited with somatostatin. Insulin binding and kinase activity of insulin receptors solubilized from vastus lateralis muscle biopsies were unaffected by hyperglycemia and/or hyperinsulinemia. Hyperinsulinemia activated the muscle glycogen synthase with a decrease in the half-maximal activation constant (A0.5) for glucose-6-phosphate (G6P) from 0.53 +/- 0.04 to 0.21 +/- 0.02 mmol/L (study A, P less than .02) and from 0.53 +/- 0.06 to 0.19 +/- 0.05 mmol/L (study C, P less than .03). In addition, the rate of glycogen synthase activation by phosphatases increased from 0.078 +/- 0.017 to 0.134 +/- 0.029 U/min/mg protein (study A, P less than .03) and from 0.082 +/- 0.013 to 0.145 +/- 0.033 U/min/mg protein (study C, P = .05). Hyperglycemia during normoinsulinemia did not affect A0.5 or phosphatase activity. In conclusion, (1) hyperinsulinemia for 2 1/2 hours increases glycogen synthase activity and activation by phosphatases independently on the glycemia; and (2) insulin receptor binding and basal and insulin-stimulated receptor kinase activity are not modified during short-term hyperinsulinemia and/or hyperglycemia.
Enzyme Activation↗
Gliclazide and insulin action in human muscle.
Sulfonylureas are widely used drugs in the treatment of NIDDM when diet treatment is unsuccessful. In addition to their pancreatic effects sulfonylureas have been reported to have insulin-like and insulin-potentiating actions in vitro with respect both to glucose transport and glycogen synthase activation in isolated adipocytes and hepatocytes from rats. Glycogen synthesis in muscle accounts for the major part of non-oxidative glucose metabolism during insulin stimulation. Treatment with gliclazide of patients with NIDDM has been shown to be associated with a potentiation of both insulin-mediated glucose disposal and insulin-stimulated glycogen synthase activity in skeletal muscle. Muscle insulin receptor binding or insulin receptor kinase activity was shown not to be affected by gliclazide treatment. Whether the improved insulin sensitivity and improved insulin action on skeletal muscle glycogen synthase during gliclazide treatment is due to a direct or an indirect action of the drug is discussed.
Animals↗
Chromosome aberrations in Norwegian reindeer calves exposed to fallout from the Chernobyl accident.
Chromosome aberrations were analysed in 1222 peripheral blood lymphocytes from 24 reindeer, Rangifer tarandus L., calves from central Norway, where considerable fallout from Chernobyl accident had occurred, and in 1532 lymphocytes from 26 calves from three different districts in Northern Norway which were not affected by fallout from the accident. Three dicentrics, two rings, and three translocations were detected in calves from the exposed area, while no dicentrics, nor rings and only one translocation were detected in the control calves. The frequency of chromatid-type aberrations and chromosome deletions did not significantly differ between the two groups. Although the present study is based on a limited number of observations, the radioactive burden in the exposed reindeer, and the differing character of the chromosome aberrations in the two groups, might indicate that certain genetic effects have occurred as a result of the Chernobyl accident in Norwegian reindeer in the most contaminated areas.
Accidents↗
High fat feeding causes insulin resistance and a marked decrease in the expression of glucose transporters (Glut 4) in fat cells of rats.
With the identification of two different glucose transporter species in adipose cells it is crucial to determine the role of these transporters in the alterations in glucose transport activity associated with different metabolic and nutritional states. In the present study we assess levels of expression of Glut 1 and Glut 4 transporters and basal and insulin-stimulated glucose transport activity in adipocytes from Sprague-Dawley rats fed standard chow (control), combined liquid diet and standard chow (overfed), high fat diet, or energy-restricted diet for 7 weeks. High fat feeding was associated with relative postprandial hypoglycemia (P less than 0.05) and hypoinsulinemia (P less than 0.05). Although the high fat fed animals had lower body weights (P less than 0.05) than control rats, their body compositions showed obesity, with 36% heavier epididymal fat pads (P less than 0.05) and a 47% increase in adipocyte volume (P less than 0.05). Fat feeding caused a 78% reduction in insulin-stimulated glucose transport per adipocyte (P less than 0.05). In parallel we found 92% and 94% reductions in Glut 4 protein and mRNA per adipocyte, respectively, (P less than 0.01) in fat-fed rats. Substantial reductions were also seen in Glut 1 protein and mRNA per fat cell in the same rats (62% and 76%, respectively; P less than 0.05). However, the changes in Glut 1 expression were of the same magnitude as changes in the cytoskeletal protein beta-actin, reflecting a decreased expression of several proteins in this nutritional state. Even though overfeeding and energy restriction brought about opposite changes in adiposity, no significant alterations were demonstrated in glucose transport rate or glucose transporter expression. The impaired insulin-stimulated glucose transport in adipose cells from high fat-fed rats occurs in the presence of a dramatic decrease in the expression of the major insulin-responsive glucose transporter (Glut 4). The reduced gene expression may be caused by chronic hypoinsulinemia and may contribute to the insulin resistance observed in this state.
Adipose Tissue↗
The effect of acute hyperglycemia on the plasma C-peptide response to intravenous glucagon or to a mixed meal in insulin-dependent diabetes mellitus.
The dose-response relationships between prestimulatory blood glucose concentration and the plasma C-peptide responses to stimulation with 1 mg of glucagon iv or a standard mixed meal were studied in 8 C-peptide positive patients with insulin-dependent diabetes mellitus. Hyperglycemia was maintained for 90 min before stimulation using a hyperglycemic clamp technique. Each test was performed at the steady state blood glucose levels approximately 5, approximately 12, and approximately 20 mmol/l. The glucose potentiation of the incremental plasma C-peptide area under the curve at the two levels of hyperglycemia in percent of the area at normoglycemia (median and range) was 343% (53-1053) (p less than 0.05) and 341% (267-1027) (p less than 0.05) after glucagon and 140% (76-227) (NS) and 251% (95-1700) (p less than 0.05) after the meal. The corresponding relative glucose potentiation of plasma C-peptide 6 min after stimulation with glucagon was 124% (100-427) (p less than 0.02) and 144% (100-209) (p less than 0.05). There was no significant difference in the degree of glucose potentiation at approximately 12 or approximately 20 mmol/l. Furthermore, there was no significant difference in the degree of glucose potentiation of the different estimated values of B-cell function. In conclusion, the plasma C-peptide responses to iv glucagon or to a standard test meal were markedly potentiated by acute hyperglycemia in insulin-dependent diabetes mellitus. No further potentiation was, however, obtained when the prestimulatory blood glucose concentration was raised above 12 mmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Impaired expression of glycogen synthase mRNA in skeletal muscle of NIDDM patients.
Based on recent studies of the abnormal physiology and biochemistry of the glycogen synthesis in skeletal muscle of non-insulin-dependent diabetes mellitus (NIDDM) patients and their first-degree relatives, the key enzyme of this pathway, glycogen synthase (GS), is considered a candidate gene in the pathogenesis of insulin resistance. Comparing matched groups of 14 NIDDM patients with 14 control subjects, we found that impaired insulin-stimulated nonoxidative glucose metabolism of peripheral tissue (P less than 0.02) and reduced total GS activity (P less than 0.05) of vastus lateralis muscle from patients with NIDDM were accompanied by a 39% reduction (P less than 0.02) in the steady state level of GS mRNA per microgram DNA of muscle. In both diabetic and control subjects, the mRNA expression of GS was unaffected after euglycemic-hyperinsulinemic clamp for 4 h. With single-stranded conformation polymorphism analysis of the entire coding sequence of the GS gene, we were unable to detect any genetic variants in a subset of eight NIDDM patients. We conclude that abnormal pretranslational regulation of the GS gene may contribute to impaired glycogen synthesis of muscle in NIDDM. Our studies give no evidence for structural changes in the coding region of the GS gene, and it is unknown if the decreased mRNA expression is due to impaired transcription or accelerated degradation of the transcript.
Blotting, Northern↗