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Oluf Pedersen

ABSTRACT. The dietary recommendations for noninsulin-dependent diabetics recently published by several national diabetes associations are reviewed and commented upon. In obese diabetics the emphasis is on an energy restriction. Moreover, all organizations agree on the advice of a decrease of the saturated fat content and an increase in the amount of starch and watersoluble, nondigestible carbohydrates in diabetic diets. Epidemiological, experimental and clinical evidences suggest that consumption of this type of diet may be less atherogenic and may improve the action of insulin on carbohydrate metabolism.

Key words: Noninsulin-dependent diabetes, diet, carbohydrates, fat, fibres, weight reduction.

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Oluf Pedersen and Henning Beck-Nielsen

ABSTRACT

Insulin binding sites were demonstrated in human mononuclear leucocytes by use of a technique which includes isolation of mononuclear leucocytes from defibrinated blood and separation of cell bound and free [125I] insulin with silicone oil.

The binding was time and temperature dependent. At 15°C equilibrium was reached after 90 min and a plateau maintained for at least 50 min. Incubations were carried out at 4°C, 15°C and 37°C. Maximal binding was obtained at 15°C. The optimum pH for insulin receptor interaction occurred at about 8. [125I] insulin binding to mononuclear leucocytes was demonstrated to be a linear function of cell number concentration over a range of 17–70× 106×ml−1. The binding was a displaceable function of native insulin concentration.

In a group of 21 young healthy persons with normal body weight we found a mean specific cell binding fraction of 1.92 ± 0.58 (s) × 10−2. Analysis of the equilibrium between insulin and its receptor revealed an apparent heterogeneity of insulin receptors.

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Elisabeth Hjøllund, Bjørn Richelsen and Oluf Pedersen

Abstract. We have described the receptor binding of A 14-labelled [125I]insulin to viable adipocytes, hepatocytes, monocytes and erythrocytes from the pig. For all cell types the binding was of high affinity, specific for insulin, the non-specific binding low and degradation of insulin in the medium was minimal. At 24°C, steady state insulin binding was achieved in all four cell types. At 37°C, steady state insulin binding could be measured to adipocytes and hepatocytes. Specific insulin binding levels and receptor affinity for blood and fat cells from the pig are comparable to that in human cells, whereas differences, especially according to affinity, exist between pig and rat cell insulin receptor binding. It is therefore concluded that the pig is a more suitable model for studies of insulin binding in man than rodents. Finally, no correlations between the individual binding levels to the different cell types were observed. Hence, measurement of insulin binding to the easier available blood cells cannot replace studies of insulin binding to target cells of insulin.

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Kristine H Allin, Trine Nielsen and Oluf Pedersen

Perturbations of the composition and function of the gut microbiota have been associated with metabolic disorders including obesity, insulin resistance and type 2 diabetes. Studies on mice have demonstrated several underlying mechanisms including host signalling through bacterial lipopolysaccharides derived from the outer membranes of Gram-negative bacteria, bacterial fermentation of dietary fibres to short-chain fatty acids and bacterial modulation of bile acids. On top of this, an increased permeability of the intestinal epithelium may lead to increased absorption of macromolecules from the intestinal content resulting in systemic immune responses, low-grade inflammation and altered signalling pathways influencing lipid and glucose metabolism. While mechanistic studies on mice collectively support a causal role of the gut microbiota in metabolic diseases, the majority of studies in humans are correlative of nature and thus hinder causal inferences. Importantly, several factors known to influence the risk of type 2 diabetes, e.g. diet and age, have also been linked to alterations in the gut microbiota complicating the interpretation of correlative studies. However, based upon the available evidence, it is hypothesised that the gut microbiota may mediate or modulate the influence of lifestyle factors triggering development of type 2 diabetes. Thus, the aim of this review is to critically discuss the potential role of the gut microbiota in the pathophysiology and pathogenesis of type 2 diabetes.

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Henning Beck-Nielsen, Oluf Pedersen and Hans Otto Lindskov

ABSTRACT

The relative importance of the insulin resistance, the decreased cellular insulin binding and the relative insulin deficiency in the pathogenesis of diabetes mellitus in obese subjects has been studied.

Ten obese diabetics were studied before and during treatment for 1 year with a 1200-1500 kcal's diet.

No change was found in the insulin response to iv injection of glucose during treatment (P > 0.1), whereas the insulin sensitivity was normalized after 1 year (P < 0.01). In parallel to the clinical normalization and the improvement of the insulin sensitivity the insulin binding to monocytes was normalized (P < 0.01).

We conclude that both the insulin resistance and the relative insulin deficiency are of decisive importance in the pathogenesis of diabetes mellitus of the obese. The insulin receptor defect seems to be one of the major factors responsible for the insulin resistance.

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Henning Beck-Nielsen, Oluf Pedersen and Hans Otto Lindskov

ABSTRACT

The aim of the present study was to examine the effect of glibenclamide on the insulin receptors, the insulin sensitivity and the insulin secretion in obese non-ketotic diabetics.

Two groups of 9 obese diabetics were studied before and after 10 days' treatment with a 1200 Kcal's diet and a 1200 kcal's diet + 10 mg/day of glibenclamide, respectively. In the group treated with diet alone we found no significant alteration of the insulin secretion pattern (P > 0.1). However, the insulin sensitivity increased 37 % (P < 0.01). Furthermore, the insulin binding to monocytes increased (P < 0.01) due to a 36% rise of the binding affinity. In the group treated with glibenclamide and diet the insulin secretory pattern was unchanged, too (P > 0.1). The insulin sensitivity, however, increased 83% (P < 0.01). Moreover, the insulin binding was raised (P < 0.01) as a result of a 80 % rise of the number of insulin receptors.

In 4 patients who were treated with diet (1200 kcal/day) plus glibenclamide and in 5 patients who were treated with diet alone (1200 kcal/day) the insulin binding to monocytes was studied during treatment for 1 year. After 1 year we found a significantly (P < 0.05) higher cellular insulin binding in the glibenclamide treated patients compared to the patients who got diet alone.

We conclude that 1) the augmentation of the insulin sensitivity is of great importance for the normalization of the diabetic state in obese, 2) the increase in insulin binding may be of importance for the increase in insulin sensitivity, 3) glibenclamide appears to enhance the insulin sensitivity through an increase in the number of insulin receptors.

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Henrik Vestergaard, Marianne Rossen, Søren A Urhammer, Jørn Müller and Oluf Pedersen

Abstract

In patients suffering from the genetic syndromes of severe insulin resistance it appears that diabetes develops when the adaptive hypersecretion of insulin fails and often these forms of diabetes will be insensitive to insulin treatment. The objective of the present study was to examine the metabolic and hormonal responses to an unchanged insulin therapy with the addition of a subcutaneous administration of recombinant human IGF-I (rhIGF-I) during (a) a short-term (2 weeks) period with rhIGF-I given twice a day in a high dose (80 μg/kg body weight) in four patients with extreme insulin-resistant diabetes mellitus and (b) during a long-term (10 weeks) period with rhIGF-I given once a day in a low dose (40 μg/kg body weight) in three of the four patients. Two siblings had known mutations in the tyrosine kinase domain of the insulin receptor and a deletion of exon 17 in part of their insulin receptor mRNA, whereas the remaining two patients were suspected to have defects at receptor and/or post-receptor sites. In the short-term study period, plasma glucose levels decreased more than 35% in response to rhIGF-I in all but one patient which was paralleled by reduced levels of serum insulin (25–50%), proinsulin (40–50%) and C-peptide (10–65%) and an improvement in glycaemic control as evaluated by decreased glycosylated haemoglobin and serum fructosamine. During the long-term study period blood glucose-lowering effects of rhIGF-I were seen after 2 weeks of treatment and fasting plasma glucose and serum insulin and C-peptide levels were decreased by 40–55% after 6 weeks in the two siblings with known insulin receptor mutations. After 10 weeks of treatment fasting plasma glucose levels were still decreased whereas fasting serum insulin and C-peptide levels were increased almost to pretreatment values. In conclusion: 2 weeks of high-dose rhIGF-I therapy in insulin-treated patients with severe insulin resistance has a marked lowering effect on fasting plasma glucose and serum insulin levels whereas the metabolic and glycaemic effects of 10 weeks of treatment with low-dose rhIGF-I may be modest and transient.

European Journal of Endocrinology 136 475–482

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Jens F. Bak, Ole Schmitz, Søren S. Sørensen, Jens Frøkjær, Torben Kjær and Oluf Pedersen

Abstract.

To examine subcellular mechanisms behind the pathogenesis of peripheral insulin resistance in chronic uremic patients, insulin receptor function and glycogen synthase activity were studied in biopsies of skeletal muscle obtained during renal transplant surgery in 9 non-diabetic uremic patients. The results were compared with values obtained in an age- and sex-matched group of subjects with normal renal function, undergoing surgery for urological or gynecological diseases. The recovery of solubilized, wheat germ agglutinin-purified insulin receptors from skeletal muscle was increased among the uremic patients: 49.3 ± 6.1 vs 31.4 ± 2.8 fmol/100 mg muscle in healthy controls (p < 0.03). Basal as well as insulin-stimulated kinase activities of the insulin receptors, expressed as phosphorylation of the synthetic peptide poly(Glu-Tyr(4:1)) were similar. In addition, the maximal activity of the glycogen synthase was enhanced in uremic muscle: 26.6 ± 2.8 vs 19.5 ± 1.8 nmol · (mg protein)−1 · min−1 (p < 0.05), whereas the half-maximal activation constant for glucose-6-phosphate was identical in the two groups. Likewise, the muscle glycogen concentrations were similar in the uremic patients and the normal controls. In conclusion, our data suggest that neither impaired insulin receptor function nor a reduced maximal glycogen synthase activity of skeletal muscle are involved in the pathogenesis of the insulin resistance of patients with chronic renal failure.

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Henning Beck-Nielsen, Oluf Pedersen, Jens Peder Bagger and Niels Schwartz Sørensen

ABSTRACT

Using [125I]insulin at 172 pmol/l (1 ng/ml) the binding of insulin to mononuclear leucocytes isolated from peripheral blood was studied.

Our present study comprised 21 healthy subjects (22–33 years old, 90–110% of ideal weight) and a comparable group of 22 obese subjects (20–37 years old, minimum 150% of ideal weight). A significant difference in insulin binding was found between the two groups, the mean specific insulin binding fraction in normals being 1.92 ± 0.58 (s) × 10−2 and that for the obese 1.19 ± 0.41 (s) × 10−2 (P < 0.01).

No correlation was found between body weight and the number of insulin receptors in the obese subjects. However, the number of insulin receptors was negatively correlated to fat cell size (P < 0.05). Insulin receptors in subjects were also negatively correlated to fasting plasma insulin (P < 0.05).

Insulin receptors were studied in 11 obese subjects before and after 10 days of fasting. A significant increase in the number of insulin receptors was observed with a simultaneous decrease in plasma insulin to normal values.

The results indicate that obesity complicated by hyperinsulinism is associated with a decrease in the number of insulin receptors compared with the normal. This finding may in part explain the decreased insulin sensitivity of the hyperinsulinaemic obese.

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Oluf Pedersen, Bjørn Richelsen, Jens Bak, Jon Arnfred, Jørgen Weeke and Ole Schmitz

Abstract. Insulin action on glucose utilization was characterized in adipocytes from 10 thyrotoxic patients, 6 hypothyroid patients and 10 age- and sex-matched control subjects. In thyrotoxic patients insulin binding at low insulin concentrations was reduced (P < 0.05) and accompanied by impaired insulin sensitivity of glucose transport (P < 0.02), glucose oxidation (P < 0.05) and lipogenesis (P < 0.05). Glucose transport and glucose oxidation rates also exhibited depressed maximal insulin responsiveness (P < 0.05). In hypothyroid patients insulin binding was reduced, too, (P < 0.05) and associated with impaired sensitivity to insulin of glucose transport (P < 0.05). Both glucose transport and lipogenesis rates showed decreased maximal insulin responsiveness (P < 0.05). In conclusion: In man, both hyper- and hypothyroidism are characterized by insulin resistance of adipocyte glucose utilization localized to insulin binding as well as to insulin-stimulated glucose transport and metabolism.