Pharmacological treatment of the obese diabetic patient.

in Diabète & Métabolisme (1993), 19(6), 547-59

Obesity is a well-known risk factor for non-insulin-dependent (or Type 2) diabetes mellitus. Consequently, reduction of weight excess comes to the front line in the prevention and management of NIDDM. It ... [more ▼]

Obesity is a well-known risk factor for non-insulin-dependent (or Type 2) diabetes mellitus. Consequently, reduction of weight excess comes to the front line in the prevention and management of NIDDM. It is only when diet and physical exercise fail that drug treatment should be considered. Pharmacological treatment of obesity should favour drugs which not only promote weight loss, by reducing caloric intake and/or increasing thermogenesis and energy expenditure, but also, and especially, improve insulin sensitivity. Serotoninergic anorectic compounds (dexfenfluramine, fluoxetine) appear to possess, to some extent, all these properties. Metformin significantly reduces insulin resistance and improves glycaemic control without inducing weight gain, and even favouring some weight loss. This biguanide is now considered as the first line drug for the obese diabetic patient. Alpha-glucosidase inhibitors may help to reduce post-prandial glucose excursions but do not promote weight loss per se. Sulfonylureas can be prescribed to an obese patient when hyperglycaemia persists despite diet and the above-mentioned oral agents, but their use should be associated with reinforcement of dietary advices in order to prevent further weight increase; it is also the case for insulin therapy. Finally, drugs specifically stimulating thermogenesis and energy expenditure, new agents sensitizing tissues to the action of insulin and various compounds interfering with lipid metabolism are currently under extensive investigation with promising preliminary results in the obese diabetic patient. In conclusion, obesity remains a major problem in the management of Type 2 diabetes mellitus and this justifies the search for new, safe and effective, pharmacological approaches. [less ▲]

Management of non-insulin-dependent diabetes mellitus.

in Drugs (1992), 44 Suppl 3

The initial management of non-insulin-dependent diabetes mellitus (NIDDM) should include patient education, dietary counselling and, when feasible, individualised physical activity. It is only when such ... [more ▼]

The initial management of non-insulin-dependent diabetes mellitus (NIDDM) should include patient education, dietary counselling and, when feasible, individualised physical activity. It is only when such measures fail that drug therapy should be considered. Dietary management of NIDDM includes a restriction in calories, and these should be appropriately distributed as carbohydrates, lipids and proteins. Supplementation of the diet with soluble fibre and supplementation with magnesium salts if hypomagnesaemia is demonstrated, is recommended. However, supplementation with fish oils or with fish oil-derived omega-3 fatty acids is not currently recommended. Oral drug therapies used in NIDDM include sulphonylurea derivatives, which are a first-line treatment in patients who are not grossly obese, metformin, which is the treatment of choice for obese patients, and alpha-glucosidase inhibitors such as acarbose, which are used mainly to reduce postprandial blood glucose peaks. These types of drugs can be used alone or in combination. Insulin therapy may be required to achieve adequate control of blood glucose levels in some patients. In several instances, it is suggested that insulin therapy be combined with sulphonylureas (essentially when residual insulin secretion is present), with metformin, or with alpha-glucosidase inhibitors. The treatment of disorders associated with NIDDM, such as obesity, hypertension or hyperlipidaemia, requires particular attention in diabetic patients, since some drugs can adversely affect glycaemic control. Oral drugs for the treatment of NIDDM include sulphonylurea derivatives used in first-line treatment in patients who are not grossly obese, metformin, which is often the treatment of choice for obese patients and, more recently, the alpha-glucosidase inhibitors, such as acarbose, which are effective in reducing the postprandial rise in blood glucose. [less ▲]

Impaired immune responses in diabetes mellitus: analysis of the factors and mechanisms involved. Relevance to the increased susceptibility of diabetic patients to specific infections.

in Diabète & Métabolisme (1992), 18(3), 187-201

The reasons why diabetic patients present with an increased susceptibility to frequent and protracted infections remain unclear. The virtual absence of epidemiological studies of the independent risk ... [more ▼]

The reasons why diabetic patients present with an increased susceptibility to frequent and protracted infections remain unclear. The virtual absence of epidemiological studies of the independent risk factors involved contrasts with the multitude of in vitro models focused on the metabolism and function of immune cells from diabetic patients. This review analyzes some of these models and their clinical relevance. The different levels of diabetes pathogenesis: genetic (Type 1), autoimmune (Type 1) and metabolic (Type 1 and Type 2) are responsible for immune abnormalities demonstrated in in vitro models. The participation of genetic and autoimmune factors has been mainly characterized on T lymphocyte function. The B8 DR3 haplotype is associated with several minor immunologic abnormalities in vitro. However, the high frequency of this haplotype in healthy individuals argues against its involvement in significant defects of antimicrobial immunity. Genetic deficiency of C4, present in 25% of Type 1 diabetic patients could, on the other hand, be responsible for opsonization defects against encapsulated pathogens. Several immunological abnormalities related to the autoimmune process preceding the onset of Type 1 diabetes mellitus, such as the depletion of memory CD4+ cells and the defective natural killer activity could transiently impair host defences against viral diseases. Several in vitro functional defects of the immune system have been correlated with the metabolic control of diabetic patients. This suggests the involvement of insulinopenia in some of the abnormalities observed. Insulinopenia-induced enzymatic defects have often been proposed to inhibit energy-requiring functions of phagocytes and lymphocytes. However, the relevance of this mechanism could be confined to patients with extremely severe metabolic abnormalities. The importance of systemic consequences of insulinopenia such as hyperglycaemia and ketosis has also been addressed. Usually, the defects induced in vitro by these factors are slight and require supraphysiologic concentrations of glucose or ketone bodies. Recent studies have shown abnormalities of signal transduction mechanisms in which insulinopenia itself and other factors such as circulating immune complexes could be involved. Despite numerous controversies, many in vitro studies of the immune cells of diabetic patients have demonstrated significant defects which bear quantitative similarities with abnormalities described in other immunodeficiency syndromes. Furthermore, several mechanisms have been proposed to link the different defects observed with the specific infections encountered in diabetic patients. [less ▲]

Squatting to standing: an unusual but powerful postural manoeuvre to investigate human arterial blood pressure regulation

in Archives of Physiology & Biochemistry (1992), 100(5), 31-51

Pulsatile insulin delivery has greater metabolic effects than continuous hormone administration in man: importance of pulse frequency.

in Journal of Clinical Endocrinology and Metabolism (1991), 72(3), 607-15

The aim of this study was to see if the greater effect of insulin on hepatic glucose output when insulin is given using 13-min pulses in man remains when the same amount of insulin is delivered using 26 ... [more ▼]

The aim of this study was to see if the greater effect of insulin on hepatic glucose output when insulin is given using 13-min pulses in man remains when the same amount of insulin is delivered using 26-min pulses. The study was performed on nine male healthy volunteers submitted to a 325 min glucose-controlled glucose iv infusion using the Biostator. The endogenous secretion of pancreatic hormones was inhibited by somatostatin. Three experiments were performed in each subject on different days and in random order. In all cases glucagon was replaced (58 ng min-1). The amounts of insulin infused were identical in all instances and were 0.2 mU kg-1 min-1 (continuous), 1.3 mU kg-1 min-1, 2 min on and 11 min off (13-min pulses) or 2.6 mU kg-1 min-1, 2 min on and 24 min off (26-min pulses). Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classic methodology using D-[3-3H] glucose infusion allowed to study glucose turnover. When compared with continuous insulin, 13-min insulin pulses induced a significantly greater inhibition of endogenous glucose production. This effect disappeared when insulin was delivered in 26-min pulses. We conclude that, in man, an adequate pulse frequency is required to allow the appearance of the greater inhibition of pulsatile insulin on endogenous glucose production. [less ▲]

Absence de benefice de l'administration intermittente de l'insuline lors d'un traitement par pompe a perfusion sous-cutanee chez le diabetique de type-1.

in Diabète & Métabolisme (1991), 17(3), 363-72

Our study is based on two constatations: 1) Hyperinsulinaemia, a possible atherogenic factor, is frequent under continuous subcutaneous insulin infusion. 2) Pulsatile intravenous insulin delivery improve ... [more ▼]

Our study is based on two constatations: 1) Hyperinsulinaemia, a possible atherogenic factor, is frequent under continuous subcutaneous insulin infusion. 2) Pulsatile intravenous insulin delivery improve the insulin's hypoglycaemic activity. To test if equivalent metabolic control can be obtained with a reduced intermittent subcutaneous infused insulin dose, we compared nocturnal metabolic control of 8 c-peptide negative type 1 diabetic patients under three experimental conditions: Continuous usual dose test (1.0 +/- 0.1 u/h); Intermittent half dose test (1.0 +/- 0.1 u/h, 30 min/h); Continuous half dose test (0.5 +/- 0.05 u/h) Five parameters were monitored: blood glucose, plasma free insulin and beta-hydroxy-butyrate, free fatty acid and glycerol plasma level. No significant differences were found between intermittent and continuous half-dose tests. We conclude that, in our experimental conditions, intermittent subcutaneous insulin infusion does not reduce the metabolic degradation induced by insulin dose reduction. [less ▲]

Thymic cryptocrine signaling and the immune recognition of self neuroendocrine functions

in Progress in NeuroEndocrinImmunology (1991), 5

Effects of ethinyl estradiol combined with desogestrel and cyproterone acetate on glucose tolerance and insulin response to an oral glucose load: a one-year randomized, prospective, comparative trial.

in American Journal of Obstetrics and Gynecology (1990), 163(1 Pt 2), 378-81

To investigate the effects of two slightly estrogen-dominant, monophasic, low-dose oral contraceptives on carbohydrate metabolism, 40 healthy young women were randomly allocated to receive either 30 ... [more ▼]

To investigate the effects of two slightly estrogen-dominant, monophasic, low-dose oral contraceptives on carbohydrate metabolism, 40 healthy young women were randomly allocated to receive either 30 micrograms of ethinyl estradiol + 150 micrograms of desogestrel, a 19-nortestosterone-derived progestin (Marvelon; n = 21) or 35 micrograms of ethinyl estradiol + 2 mg of cyproterone acetate, a 17-acetoxyprogesterone derivative (Diane-35; n = (19) for a prospective observation period of 1 year. At baseline, 6, and 12 months, blood glucose, plasma insulin, and plasma C-peptide levels were measured during an oral glucose tolerance test. Although the changes were absent (Marvelon) or minimal (Diane-35) at 6 months, both groups had a slight increase in blood glucose levels at 12 months; overall glucose tolerance remaining, however, within the normal range. Plasma insulin levels remained unchanged in the Diane-35-group, which suggested increased insulin resistance, but were significantly decreased in the Marvelon group despite significant rises in plasma C-peptide levels. Comparison of plasma C-peptide and insulin changes suggests enhanced pancreatic insulin secretion and increased hepatic insulin metabolism with both Marvelon and Diane-35. [less ▲]

Alimentation avant, pendant et après l'exercice physique chez le sujet normal et diabétique

in Journées Annuelles de Diabetologie de l'Hôtel-Dieu (1990)

Insulin versus insulin plus sulfonylureas in type 2 diabetic patients with secondary failure to sulfonylureas.

in Diabetes Research & Clinical Practice (1989), 6(4), 33-4242-3

According to the modern pathophysiological understanding of type 2 diabetes and the mechanisms of sulfonylurea action, combined insulin-sulfonylurea therapy appears to be an interesting alternative for ... [more ▼]

According to the modern pathophysiological understanding of type 2 diabetes and the mechanisms of sulfonylurea action, combined insulin-sulfonylurea therapy appears to be an interesting alternative for treating diabetic patients with secondary failure to sulfonylureas. From its revival in the early 1980s, combination therapy has been shown to have a positive effect on blood glucose control although initially published clinical studies, generally open and uncontrolled, have been widely criticized. Several recent well-designed studies confirmed these favorable results, with better glucose profiles and/or decreased insulin needs, which were shown to persist after 1 year or more. Most of the studies investigating the mechanism of action indicate that the effect is mainly due to stimulation of the residual insulin secretion with minimal or no effect on insulin sensitivity. The risk of hypoglycemic episodes is rather small when insulin doses are adapted at the beginning of the combined therapy. Effects on lipid metabolism are minimal and controversial. Thus, insulin-sulfonylurea treatment may be a safe and effective solution in type 2 diabetic patients with secondary failure to sulfonylureas, particularly in those with significant residual endogenous insulin secretion. The additional cost of such combined therapy should be weighed against the potential advantages of better metabolic control. [less ▲]