Effects of ingested fructose and infused glucagon on endogenous glucose production in obese NIDDM patients, obese non-diabetic subjects, and healthy subjects.

in Diabetologia (1996), 39(5), 580-6

Increased endogenous glucose production (EGP) and gluconeogenesis contribute to the pathogenesis of hyperglycaemia in non-insulin-dependent diabetes mellitus (NIDDM). In healthy subjects, however, EGP ... [more ▼]

Increased endogenous glucose production (EGP) and gluconeogenesis contribute to the pathogenesis of hyperglycaemia in non-insulin-dependent diabetes mellitus (NIDDM). In healthy subjects, however, EGP remains constant during administration of gluconeogenic precursors. This study was performed in order to determine whether administration of fructose increases EGP in obese NIDDM patients and obese non-diabetic subjects. Eight young healthy lean subjects, eight middle-aged obese NIDDM patients and seven middle-aged obese non-diabetic subjects were studied during hourly ingestion of 13C fructose (0.3 g.kg fat free mass-1.h-1) for 3 h. Fructose failed to increase EGP (measured with 6,6 2H glucose) in NIDDM (17.7 +/- 1.9 mumol.kg fat free mass-1.min-1 basal vs 15.9 +/- 0.9 after fructose), in obese non-diabetic subjects (12.1 +/- 0.5 basal vs 13.1 +/- 0.5 after fructose) and in lean healthy subjects (13.3 +/- 0.5 basal vs 13.8 +/- 0.6 after fructose) although 13C glucose synthesis contributed 73.2% of EGP in lean subjects, 62.6% in obese non-diabetic subjects, and 52.8% in obese NIDDM patients. Since glucagon may play an important role in the development of hyperglycaemia in NIDDM, healthy subjects were also studied during 13C fructose ingestion + hyperglucagonaemia (232 +/- 9 ng/l) and during hyperglucagonaemia alone. EGP increased by 19.8% with ingestion of fructose + glucagon (p < 0.05) but remained unchanged during administration of fructose or glucagon alone. The plasma 13C glucose enrichment was identical after fructose ingestion both with and without glucagon, indicating that the contribution of fructose gluconeogenesis to the glucose 6-phosphate pool was identical in these two conditions. We concluded that during fructose administration: 1) gluconeogenesis is increased, but EGP remains constant in NIDDM, obese non-diabetic, and lean individuals; 2) in lean individuals, both an increased glucagonaemia and an enhanced supply of gluconeogenic precursors are required to increase EGP; this increase in EGP occurs without changes in the relative proportion of glucose 6-phosphate production from fructose and from other sources (i.e. glycogenolysis + gluconeogenesis from non-fructose precursors). [less ▲]

Assessment of residual insulin secretion in diabetic patients using the intravenous glucagon stimulatory test: methodological aspects and clinical applications.

in Diabètes & Métabolism (1996), 22(6), 397-406

Defective insulin secretion plays a crucial role in insulin-dependent (Type 1) and non-insulin-dependent (Type 2) diabetes mellitus as well as in many secondary forms of the disease. Glucagon is a potent ... [more ▼]

Defective insulin secretion plays a crucial role in insulin-dependent (Type 1) and non-insulin-dependent (Type 2) diabetes mellitus as well as in many secondary forms of the disease. Glucagon is a potent stimulus for the islet beta-cell, and intravenous bolus injection of 1 mg glucagon has been widely used to assess endogenous insulin secretion for clinical or research purposes. Plasma C-peptide levels (less commonly insulin) are usually measured immediately before and 6 min after glucagon injection. The C-peptide response to glucagon is well-correlated with the beta-cell response to mixed meals or other stimuli commonly used to characterize endogenous insulin secretion (oral or intravenous glucose, standard meals, arginine, etc.) and has the advantage of shorter duration and simple standardization. The glucagon test shows good intra-subject reproducibility, although in diabetic patients it may be influenced by variable prevailing blood glucose levels. Several applications of the glucagon test have been developed. In Type 1 diabetes, the glucagon test has been used to discriminate between patients with and without residual insulin secretion. This can be especially important during the first few months, or even years, following initiation of insulin therapy when attempts to stop the immunological destruction of the beta-cell are made. Assessment of endogenous insulin secretion is also important after pancreas or islet transplantation. In patients with Type 2 diabetes mellitus, in which residual endogenous insulin secretion is common, characterization of the disease may help in the choice of therapy for the individual patient (insulin, sulphonylureas or combined therapy). Thus, the glucagon test is a simple, reliable and useful tool for clinical evaluation of diabetes mellitus. [less ▲]

Insulin action in man.

in Diabètes & Métabolism (1996), 22(2), 105-10

Insulin action is crucial for the regulation of glucose metabolism. Insulin plays a key role in suppressing endogenous glucose production by the liver, both in fasting and postprandial states. Insulin is ... [more ▼]

Insulin action is crucial for the regulation of glucose metabolism. Insulin plays a key role in suppressing endogenous glucose production by the liver, both in fasting and postprandial states. Insulin is also necessary for the maintenance of normal rates of glucose oxidation and storage in insulin-sensitive tissues and for the prevention of excessive gluconeogenic substrate production. Various methods have been developed to assess insulin action in vivo, essentially at liver and muscle sites. Such methods evaluate the effect of exogenous or endogenous insulin, using respectively the open-loop approach (interruption of the feedback loop by inhibiting endogenous insulin secretion) or the closed-loop approach (mathematical modelling of the insulin-glucose feedback loop). Knowledge of the successive steps of cellular insulin action has markedly improved during the last ten years. Preceptor, receptor and postreceptor levels need to be considered since they may be affected in insulin-resistant states. This general progress in the understanding of insulin action in man improves our approach to the complex pathophysiology of non-insulin-dependent diabetes mellitus and opens up new prospects for treatment of the insulin-resistant syndrome which is associated with several atherosclerotic risk factors. [less ▲]

Comment explorer la sensibilite a l'insuline chez l'homme?

in Annales d'Endocrinologie (1995), 56(5), 523-30

The two most widely used methods for studying insulin sensitivity in man are the euglycaemic hyperinsulinaemic clamp and the intravenous glucose tolerance test with minimal model assessment. The glucose ... [more ▼]

The two most widely used methods for studying insulin sensitivity in man are the euglycaemic hyperinsulinaemic clamp and the intravenous glucose tolerance test with minimal model assessment. The glucose clamp is the reference method, well validated and easy to interpret, which allows various extensions to the basic experimental procedure in order to obtain more valuable information on the specific effects of insulin on the various aspects of glucose metabolism. However, it is time-consuming and labour-intensive. In contrast, the intravenous glucose tolerance test is easier to perform, but its interpretation is much more difficult and requires a modeling approach called the "minimal model". If the intravenous glucose tolerance test probably represents a good screening test, mainly on a population basis, the glucose clamp still remains the gold standard method to study insulin sensitivity in man. [less ▲]

Glucose handling, diabetes and ageing.

in Hormone Research (1995), 43(1-3), 52-7

The relationship between ageing and glucose homeostasis is still an open debate. In fact, the mechanisms by which glucose metabolism is progressively impaired with increasing age are not completely ... [more ▼]

The relationship between ageing and glucose homeostasis is still an open debate. In fact, the mechanisms by which glucose metabolism is progressively impaired with increasing age are not completely understood. In the present report we have reviewed the possible mechanisms (impaired insulin secretion and action, role of the environmental factors) which may lead to the impairment in glucose handling associated with ageing. We also point out that not all aged subjects are glucose intolerant; in fact, it has been suggested that only those aged subjects who present more than one pathological finding do in fact develop impaired glucose handling. [less ▲]

Cellular and molecular aspects of thymic T-cell education to neurohypophysial peptides

in Yoshida, Sho; Saito, Toshikazu; Kurokawa, Kiyoshi (Eds.) Neurohypophysis - Recent Progress of Vasopressin and Oxytocin Research (1995)

Our studies have shown that oxytocin (OT) is the dominant peptide of the neurohypophysial (NHP) family that is expressed by thymic epithelial/nurse cells (TEC/TNC). Both in specific RIA and ICC analyses ... [more ▼]

Our studies have shown that oxytocin (OT) is the dominant peptide of the neurohypophysial (NHP) family that is expressed by thymic epithelial/nurse cells (TEC/TNC). Both in specific RIA and ICC analyses, vasopressin (VP) immunoreactivity is considerably lower in TEC. OT is not secreted by TEC/TNC, but it is presented as the self antigen of the NHP family to developing pre-T cells. The process of T-cell education in recognizing the NHP family involves an active cooperation between this neuroendocrine gene/protein family and the immunoglobulin family. This cooperation is illustrated by the identification in plasma membranes of human TEC of a 55-kDa protein bearing a neurophysin (10 kDa), as well as a MHC class I heavy chain-related domain (45 kDa). Since both OT and VP genes are transcribed in the thymus, the site of this cooperation should be located at posttranscriptional level. From these data, it appears that thymic T-cell education to the NHP family involves specific pathways which are not strictly superimposible to those dlineated using peripheral dedicated APC. Although MHC class I pathways are needed, it appears that thymic T-cell education to NHP self is not restricted in an allelic fashion. This offers significant advantages for the selection of the human T-cell repertoire. Furthermore, the absence of a tight MHC allelic restriction in the process of T-cell education to neuroendocrine self opens novel perpectives for the prevention of autoimmune endocrine disorders such as insulin-dependent diabetes mellitus. [less ▲]

Amylin/islet amyloid polypeptide: biochemistry, physiology, patho-physiology.

in Diabète & Métabolisme (1995), 21(1), 3-25

Amylin is a 37 amino-acid peptide mainly produced by the islet beta-cell. Aggregation of amylin is partly responsible for amyloid formation. Amyloid deposits occur both extracellularly and intracellularly ... [more ▼]

Amylin is a 37 amino-acid peptide mainly produced by the islet beta-cell. Aggregation of amylin is partly responsible for amyloid formation. Amyloid deposits occur both extracellularly and intracellularly and may contribute to beta-cell degeneration. Amylin is packed in beta-cell granules and cosecreted with insulin in response to the same stimuli but, unlike other beta-cell products, it is produced from specific a gene on chromosome 12. Basal, plasma amylin concentrations are around 5 pM, and increase fourfold after meals or glucose. Higher levels are found in cases of insulin resistance, obesity, gestational diabetes and in some patients with NIDDM. Low or absent levels are found in insulin-dependent diabetic patients. There are similarities between amylin and non beta-cell peptides such as calcitonin gene related peptides (CGRP). They may bind to the same receptor, determine similar post-receptor phenomena and qualitatively similar actions but with different degree of potency. The actions of amylin are multiple and mostly exerted in the regulation of fuel metabolism. In muscle, amylin opposes glycogen synthesis, activates glycogenolysis and glycolysis (increasing lactate production). Consequently, amylin increases lactate output by muscle and increases the plasma lactate concentration. In fasting conditions, this lactate may serve as a gluconeogenic substrate for the liver, contributing to replenish depleted glycogen stores and to increase glucose production. In non-fasting conditions, lactate can be transformed by liver in triglycerides. It is not clear at present whether amylin actions on the liver are direct or mediated by changes in circulating metabolites. A probably indirect effect of amylin in muscle is to decrease insulin- (or glucose)-induced glucose uptake, which may contribute to insulin resistance. Other actions include inhibition of glucose-stimulated insulin secretion and, in general, actions mimicking CGRP effects. Some of these actions are seen at supraphysiological concentrations. The physiopathological consequences of amylin deficiency, or excess are under active by investigated. [less ▲]

Antihyperglycaemic agents. Drug interactions of clinical importance.

in Drug Safety : An International Journal of Medical Toxicology & Drug Experience (1995), 12(1), 32-45

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) affects middle-aged or elderly people who frequently have several other concomitant diseases, especially obesity, hypertension, dyslipidaemias ... [more ▼]

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) affects middle-aged or elderly people who frequently have several other concomitant diseases, especially obesity, hypertension, dyslipidaemias, coronary insufficiency, heart failure and arthropathies. Thus, polymedication is the rule in this population, and the risk of drug interactions is important, particularly in elderly patients. The present review is restricted to the interactions of other drugs with antihyperglycaemic compounds, and will not consider the mirror image, i.e. the interactions of antihyperglycaemic agents with other drugs. Oral antihyperglycaemic agents include sulphonylureas, biguanides--essentially metformin since the withdrawn of phenformin and buformin--and alpha-glucosidase inhibitors, acarbose being the only representative on the market. These drugs can be used alone or in combination to obtain better metabolic control, sometimes with insulin. Drug interactions with antihyperglycaemic agents can be divided into pharmacokinetic and pharmacodynamic interactions. Most pharmacokinetic studies concern sulphonylureas, whose action may be enhanced by numerous other drugs, thus increasing the risk of hypoglycaemia. Such an effect may result essentially from protein binding displacement, inhibition of hepatic metabolism and reduction of renal clearance. Reduction of the hypoglycaemic activity of sulphonylureas due to pharmacokinetic interactions with other drugs appears to be much less frequent. Drug interactions leading to an increase in plasma metformin concentrations, mainly by reducing the renal excretion or the hepatic metabolism of the biguanide, should be avoided to limit the risk of hyperlactaemia. Owing to its mode of action, pharmacokinetic interferences with acarbose are limited to the gastrointestinal tract, but have not been extensively studied yet. Pharmacodynamic interactions are quite numerous and may result in a potentiation of the hypoglycaemic action or, conversely, in a deterioration of blood glucose control. Such interactions may be observed whatever the type of antidiabetic treatment. They result from the intrinsic properties of the coprescribed drug on insulin secretion and action, or on a key step of carbohydrate metabolism. Finally, a combination of 2 to 3 antihyperglycaemic agents is common for treating patients with NIDDM to benefit from the synergistic effect of compounds acting on different sites of carbohydrate metabolism. Possible pharmacokinetic interactions between alpha-glucosidase inhibitors and classical antidiabetic oral agents should be better studied in the diabetic population. [less ▲]

Modified glucagon test allowing simultaneous estimation of insulin secretion and insulin sensitivity: application to obesity, insulin-dependent diabetes mellitus, and noninsulin-dependent diabetes mellitus.

in Journal of Clinical Endocrinology and Metabolism (1995), 80(2), 393-9

The aim of this study was to describe an adaptation of the glucagon test allowing the simultaneous characterization of insulin secretion and sensitivity. A glucagon test (1 mg/m2) was performed in healthy ... [more ▼]

The aim of this study was to describe an adaptation of the glucagon test allowing the simultaneous characterization of insulin secretion and sensitivity. A glucagon test (1 mg/m2) was performed in healthy subjects (n = 11), obese patients (n = 5), insulin-dependent diabetics (n = 9), nonobese noninsulin-dependent diabetics (n = 7), and overweight noninsulin-dependent diabetics (n = 8). Previously, they had been connected to the Biostator, modified for continuous blood collection. Endogenous insulin secretion induced by glucagon was derived from integrated C-peptide concentrations. An index of insulin sensitivity was obtained by dividing the rate of decrease in blood glucose by the total amount of insulin entering the circulation (secreted+infused by the Biostator). The indices of insulin sensitivity obtained in the above groups of subjects were, respectively, 0.064 +/- 0.006, 0.030 +/- 0.006, 0.037 +/- 0.007, 0.021 +/- 0.006, and 0.016 +/- 0.002 mmol/L.U.min (P < 0.001). The estimated insulin secretion values in the 20 min following glucagon injection were, respectively, 0.38 +/- 0.05, 0.65 +/- 0.08, 0.05 +/- 0.01, 0.26 +/- 0.15, and 0.30 +/- 0.07 U (P < 0.001). The insulin sensitivity index obtained from this test correlated with the glucose MCR obtained from a euglycemic glucose clamp (r = 0.816; P < 0.001; n = 12). C-Peptide levels after glucagon administration were also significantly correlated with the estimated endogenous insulin secretion (r = 0.808; P < 0.001; n = 30). This adaptation of the classical glucagon test is an efficient and simple method to simultaneously evaluate insulin secretion and insulin sensitivity. [less ▲]

Short administration of metformin improves insulin sensitivity in android obese subjects with impaired glucose tolerance.

in Diabetic Medicine : A Journal of the British Diabetic Association (1995), 12(11), 985-9

In a double-blind, randomized, cross-over study, the metabolic effects of a short treatment with metformin (2 x 850 mg day-1 for 2 days and 850 mg 1 h before evaluation) were compared to those of placebo ... [more ▼]

In a double-blind, randomized, cross-over study, the metabolic effects of a short treatment with metformin (2 x 850 mg day-1 for 2 days and 850 mg 1 h before evaluation) were compared to those of placebo in 15 obese subjects (BMI: 33.2 +/- 0.9 kg m-2), with abdominal distribution of adipose tissue and impaired glucose tolerance. An intravenous glucose tolerance test (0.3 g glucose kg-1) was performed after each period of treatment. Areas under the curve (AUC0-180 min) were calculated for plasma glucose, insulin, and C-peptide levels. Glucose tolerance was estimated by the coefficient of glucose assimilation (KG). Insulin sensitivity (SI) and glucose effectiveness (SG) indices were calculated using Bergman's minimal model. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide levels and insulin metabolic clearance rate (MCR) was estimated by dividing AUC 1SR by AUC insulin. Fasting plasma insulin levels were reduced after metformin (89.3 +/- 15.9 vs 112.4 +/- 24.3 pmol l-1; p = 0.04). AUC glucose, KG and SG were similar in both tests. However, AUC insulin was reduced (39.7 +/- 6.5 vs 51.8 +/- 10.4 nmol min l-1; p = 0.02), while SI (6.98 +/- 1.14 vs 4.61 +/- 0.42 10(-5) min-1 pmol-1 l; p = 0.03) and insulin MCR (715 +/- 116 vs 617 +/- 94 ml min-1 m-2; p = 0.03) were increased after metformin. The demonstration that metformin rapidly improves insulin sensitivity should encourage further research to evaluate the long-term effects of metformin in android obese subjects with impaired oral glucose tolerance. [less ▲]