[Obesity and type 2 diabetes]. / Obésité et diabète de type 2.

Obesity is an epidemic disease associated with numerous cardiovascular risk factors as diabetes mellitus, dyslipidemia, hypertension. Insulin resistance seems to be an important promoter for the development of most of these abnormalities. Besides genetic background, obesity, especially abdominal adiposity, is by far the most important factor for the development of type 2 diabetes. The treatment of a diabetic obese subject begins with diet and regular physical activity, eventually with a psychological support. In case of failure of such lifestyle approach alone, addition of drug therapy should be considered. It may include pharmacological agents able to promote weight loss (orlistat, sibutramine, possibly rimonabant) and/or antihyperglycaemic compounds capable of reducing insulin resistance (metformin, glitazones, acarbose). In case of severe/morbid obesity complicated with type 2 diabetes not well controlled with medical means, bariatric surgery is the only treatment that can induce an important and sustained weight loss, associated with marked improvement of metabolic control and amelioration of overall prognosis.

Intact cross-talk between insulin secretion and insulin action after postgastroplasty recovery of ideal body weight in severely obese patients.

Most reports investigating the hormonal and metabolic effects of bariatric surgery studied obese subjects after partial weight loss only. Nevertheless, all studies showed significant improvements of insulin secretion, action, clearance and inhibition of its own secretion, although the parallel kinetics of all these changes remained questionable. Using the intravenous glucose tolerance test, we demonstrated a full normalization of insulin secretion, action on glucose metabolism and clearance in eight obese women who recovered and maintained ideal body weight following gastroplasty. Reciprocal changes were observed between postglucose acute insulin secretion and insulin-mediated glucose disposal so that the so-called disposition index (product of these two variables) remained unchanged after vs before gastroplasty in those individuals with normal glucose tolerance. These favourable results should encourage obtaining a drastic and sustained weight loss in patients with severe obesity at risk of developing type II diabetes.

[Prevention of type 2 diabetes: lifestyle changes or pharmacological interventions?]. / Prévention du diabète de type 2: style de vie ou médicaments?

The World Health Organisation strongly recommends strategies for the prevention of type 2 diabetes, knowing the epidemics of the disease and its strong association with that of obesity. Several intervention studies, in China ("Da-Qing Study"), in Europe ("Malmö study", "Finnish Diabetes Prevention Study") and in the United States ("Diabetes Prevention Program"), showed that lifestyle change are able to reduce by around 50% the incidence of type 2 diabetes in at risk individuals. Various pharmacological approaches have also proven their efficacy in preventing type 2 diabetes, but in most cases with less impressive reductions, between 25% and 35%. It is the case for metformin, acarbose, orlistat or various inhibitors of the renin-angiotensin system. After the report of promising results with troglitazone, large prospective studies are ongoing to test the efficacy of rosiglitazone and pioglitazone in such an indication, two insulinsensitizers of the thiazolidinedione family. We will briefly described the main results of intervention studies to prevent type 2 diabetes in at risk subjects, because of the presence of obesity, impaired glucose tolerance and/or arterial hypertension.

[Postprandial hyperglycemia. II. Pharmacological approaches]. / L'hyperglycémie post-prandiale. II. Approches thérapeutiques médicamenteuses.

Besides dietary approaches, various pharmacological means have been recently developed in order to better control postprandial hyperglycaemia. This objective may be obtained: 1) by slowing down the intestinal absorption of carbohydrates; 2) by insuring a better insulin priming soon after the meal; and 3) by inhibiting post-prandial glucagon secretion or action. Some hormones (amylin, glucagon-like peptide-1) can slow gastric emptying while alpha-glucosidase inhibitors (acarbose, miglitol) retard intestinal digestion and resorption of complex carbohydrates. A more physiological post-meal profile of insulin may be obtained in type 2 diabetes by using new insulin secretagogues of the glinide family (repaglinide, nateglinide) with an earlier and shorter insulinotropic action or, mainly in type 1 diabetes but also in type 2 diabetes, by using short-acting insulin analogues (lispro. Asp B28) or inhated insulin the action of which is faster than that of subcutaneous insulin. Post-prandial glucagon secretion can be inhibited by amylin. GLP-1 or insulin while other glucagon antagonists are currently in development.

[Clinical case of the month. Natural history of morbid obesity: towards insulin-requiring type 2 diabetes and reversal after bariatric surgery]. / Le cas clinique du mois. L'histoire naturelle d'une obésité morbide: aller vers le diabète de type 2 insulinorequérant et retour après chirurgie bariatrique.

Morbid obesity is a crucial risk factor in the development of type 2 diabetes and is often associated with a metabolic syndrome closely linked to insulin resistance. This case report illustrates the natural history of morbid obesity, starting during the adolescence and ending with an extremely severe type 2 diabetes at the age of 40. Numerous attempts of weight loss with various medical approaches failed and diabetes mellitus rapidly became insulin-requiring in a context of extreme insulin resistance. Finally, the patient was submitted to a gastric bypass which resulted in a drastic weight loss over 50 kg during the year following surgery without any significant side-effects or complications. Type 2 diabetes almost disappeared and the classical markers of insulin resistance were markedly improved. This clinical case clearly demonstrates that successful management of obesity with bariatric surgery can reverse severe type 2 diabetes.

Minimal influence of the time interval between injection of regular insulin and food intake on blood glucose control of type 1 diabetic patients on a basal-bolus insulin scheme.

The present study aimed at investigating the influence of the time interval between injection of regular insulin and meal ingestion on postprandial glucose changes and overall blood glucose control in patients with type 1 diabetes on intensive insulin therapy. Fifteen C-peptide negative subjects were submitted, in a randomized order, to two 6-week treatment periods in which regular insulin was injected either 5 minutes or 30 minutes before each of the three main meals, in combination with a bedtime NPH insulin injection. The changes in plasma glucose excursions following a breakfast test (Cmax, Tmax, Cmin, Tmin, AUC0-240 min) were similar in the two experimental protocols. Furthermore, no significant changes were observed in daily insulin dosages nor in glucose profiles obtained using home blood glucose monitoring. Only a tendency to a greater 90-minutes postprandial increase in blood glucose levels was observed when regular insulin was injected 5 minutes rather than 30 minutes before meal. Glycated haemoglobin levels were similar after each treatment period (7.6 +/- 0.2% versus 7.5 +/- 0.2%; NS) and no differences in the incidence or severity of hypoglycaemic episodes were noticed between the two insulin schemes. In conclusion, in type 1 diabetic patients who are rather well controlled with a basal-bolus insulin scheme, the injection of regular insulin 30 minutes before each main meal provides no significant advantage as compared to the injection of regular insulin 5 minutes before meal.

[How I treat ... an individual with severe obesity and metabolic abnormalities with gastroplasty]. / Comment je traite ... une obésité sévère et ses anomalies métaboliques par une gastroplastie.

Severe obesity, defined as a body mass index > or = 35 kg/m2, is frequently associated with various biological abnormalities, particularly in the presence of intra-abdominal adiposity. The most important disorders belong to the so-called insulin resistance syndrome, metabolic syndrome or syndrome X: hyperinsulinaemia, impaired glucose tolerance or type 2 diabetes, dyslipidaemias, hyperuricaemia, hyperfibrinogenaemia. All these metabolic abnormalities are considered as cardiovascular risk factors. They are also correlated with the severity of the liver steatosis which is commonly observed in individuals with severe obesity. We report our experience of the evolution of these metabolic abnormalities after a marked weight loss induced by gastroplasty. We will analyse the favourable effects of bariatric surgery on insulin sensitivity, biological components of the metabolic syndrome, type 2 diabetes and liver steatosis.

[Pharmacy-clinics medication of the month. Orlistate (xenical)]. / Pharma-clinics le médicament du mois. L'orlistat (xenical).

Orlistat (tetrahydrolipstatin), launched by Roche under the trade name Xenical, is a selective inhibitor of pancreatic and gastro-intestinal lipases. It reduces the digestion of dietary fat and its resorption through digestive mucosa by around 30%. It is indicated, at a dose of 3 x 120 mg/day (one dose with each meal) and together with a moderately low-calorie and low-fat diet, for the treatment of obesity. It has been shown, in placebo-controlled two-year trials, to almost double the number of obese subjects who succeed in loosing at least 10% of initial body weight. Independently, it contributes to decrease serum cholesterol levels by 6-10%. Because of its mechanism of action, this drug can induce intestinal side-effects which tend to decrease with time and with the reduction of fat intake, thus improving diet compliance.

[Viral implications in the etiopathogenesis of type 1 diabetes: current update]. / Implications virales dans l'étiopathogénie du diabète de type 1: données actuelles.

Type 1 diabetes mellitus results from autoimmune destruction of pancreatic beta cells. After having described genetic, immunological and metabolic factors, some researchers have hypothezised that environmental factors might trigger the autoimmune process. Based on epidemiological, anatomoclinical and animal studies, they suggest a role for virus infections.

[Pharma clinics. How I treat...a diabetic patient with severe obesity]. / Pharma clinics. Comment je traite ... un patient diabétique avec obésité sévère.

Obesity plays a crucial role in type 2 diabetes pathophysiology and a major weight loss markedly improves glycaemic control. The common failure of classical treatments leads to the use of more aggressive weight-reduction approaches, such as very-low-calorie diets (VLCDs), anti-obesity drugs or even bariatric surgery. VLCDs are very successful in the short-term but rather disappointing in the long-term. Anti-obesity compounds only induce a modest mean weight reduction, even if some patients appear to be better responders. Interestingly, serotoninergic agents increase insulin sensitivity and glycaemic control, independently of weight loss. Bariatric surgery provides the most impressive results. In well-selected subjects, gastroplasty (either vertical ring gastroplasty or adjustable silicone gastric banding) generally induces a considerable weight loss which results in a remarkable and sustained glycaemic control improvement and allows the reduction, or even the suppression, of any antidiabetic treatment. This ultimate solution should not be neglected after failure of medical approaches, provided that the indication is correct, the surgical procedure is performed in a specialized centre and the followup is well organized by a multidisciplinary team.

Plasma leptin levels, insulin secretion, clearance and action on glucose metabolism in anorexia nervosa.

From a metabolic point of view, anorexia nervosa may be viewed as a mirror image of obesity. We compared insulin secretion, clearance and action on glucose metabolism during an intravenous glucose tolerance test in nine women with anorexia nervosa and in nine age-matched normal-weight controls. Insulin secretion (ISR) was derived by deconvolution of plasma C-peptide levels, insulin clearance (MCR(I)) was obtained by dividing the area under the curve (AUC(0-180 min)) of ISR by the corresponding AUC of plasma insulin levels, insulin sensitivity (S(I)) and glucose effectiveness index (S(G)) were calculated by Bergman's minimal model. The anorectic women had markedly lower BMI values (13.7+/-0.6 vs 23.2+/-0.8 kg/m2, p<0.0001) and serum basal leptin levels (2.8+/-0.6 vs 8.9+/-1.8 ng/mL, p=0.005) than control women. The anorectic women exhibited clear-cut lower fasting and post-glucose plasma insulin levels but similar corresponding plasma C-peptide concentrations when compared to controls. Consequently, ISR was similar in both groups while MCR(I) was significantly increased in anorexia nervosa (MCR(I): 3320+/-881 vs 822+/-79 mL x min(-1) x m(-2), p<0.02). The index S(I) tended to be higher in anorectic women than in normal-weight subjects, but without reaching the level of statistical significance because of a high between-subject variability (20.2+/-5.7 vs 12.5+/-2.2 10(-5) x min(-1)/pmol x L(-1), NS). The index S(G) was similar in both groups (0.022+/-0.004 vs 0.018+/-0.002 min(-1), NS). In conclusion, low plasma insulin levels observed in women with anorexia nervosa result from high MCR(I) rather than from depressed insulin secretion. Insulin sensitivity is not systematically increased and glucose effectiveness is unchanged in anorectic women when compared to normal-weight controls.

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

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.

Glucose metabolism in obese subjects: lessons from OGTT, IVGTT and clamp studies.

Impaired glucose tolerance and overt diabetes are more frequent in presence than in absence of obesity. In obese subjects, glucose tolerance can be maintained within the normal range by compensating for insulin resistance by peripheral hyperinsulinism, the latter resulting from both increased insulin secretion and reduced insulin clearance. Impaired glucose tolerance is observed when insulin resistance is associated to impaired first-phase insulin response, which results in a significant increase in plasma glucose levels and a late insulin hyperresponsiveness. Both hyperinsulinaemia and hyperglycaemia are then able to overcome peripheral insulin resistance and impaired glucose disposal. When a more marked defect in insulin secretion is present, hyperglycaemia progresses, probably due to an additional participation of impaired suppression of hepatic glucose output. Overt diabetes then occurs with persistent post-absorptive hyperglycaemia. All these abnormalities can be reversed after a marked weight loss and recovery of ideal body weight, arguing for acquired rather than inherited metabolic defects in presence of morbid obesity. If a sufficient weight reduction can not be obtained, pharmacological approaches may be considered to improve insulin resistance of obese subjects, especially those with impaired glucose tolerance or overt diabetes.

Postgastroplasty recovery of ideal body weight normalizes glucose and insulin metabolism in obese women.

To study the metabolic effects of normalizing body weight, a frequently sampled iv glucose tolerance test (0.3 g/kg) was performed before [body mass index (BMI), 37.7 +/- 0.5 kg/m2] and 14 +/- 2 months after successful gastroplasty (BMI, 23.7 +/- 0.6 kg/m2) in eight obese women and, for comparison, in eight age- and weight-matched nonobese control women (BMI, 23.6 +/- 0.7 kg/m2). All subjects had normal oral glucose tolerance. The insulin secretion rate (ISR) was derived by deconvolution of plasma C-peptide levels and the insulin MCR (MCRI) by dividing the 0-180 min area under the curve (AUC) of ISR by that of plasma insulin levels (IRI). The insulin sensitivity index (SI) and the glucose effectiveness index (SG) were calculated using Bergman's minimal model. Before gastroplasty, obese subjects showed higher AUC-IRI (P < 0.001) and AUC-ISR (P < 0.02), lower MCRI (P < 0.005) and SI (P < 0.002), but similar SG values, compared to nonobese controls. After gastroplasty, the AUC-IRI dramatically decreased, due to both a reduction of AUC-ISR (from 58,252 +/- 8,437 to 36,675 +/- 4,274 pmol; P < 0.05) and an increase in MCRI (from 658 +/- 117 to 1,299 +/- 127 mL/min.m-2; P < 0.02). SI significantly rose from 4.74 +/- 0.74 to 9.15 +/- 0.96 10(-5) min-1/pmol.L (P < 0.01), whereas SG remained unchanged. All of these parameters became similar to those in nonobese controls (respectively, 32,522 +/- 3,458, 1,180 +/- 101, and 8.48 +/- 1.25; all P = NS). In conclusion, after gastroplasty-induced normalization of body weight, postobese women recover normal insulin secretion, clearance, and action on glucose metabolism.

[How to explore insulin sensitivity in man?]. / Comment explorer la sensibilité á l'insuline chez l'homme?

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.