[Reappraisal of metformin : less restrictions and more potential indications]. / La metformine revisitée : moins de restrictions et davantage d'indications.

While commercialized since over 60 years, metformin is still the first-line drug recommended for the management of type 2 diabetes and is thus today the first glucose-lowering agent used worldwide. Despite this long experience, metformin retains its mysteries, especially regarding the underlying mechanisms responsible for its antidiabetic activity and other potential beneficial effects. During the last years, some contra-indications of metformin use have been at least partially withdrawn while new indications have been recognized. Furthermore, interesting prospects have been reported in important, although unexpected, medical areas such as cancer and neurodegenerative diseases. However, promising results in animal studies and observational human studies have now to be confirmed in well conducted randomized controlled trials.

Commercialisée depuis plus de 60 ans, la metformine est recommandée en première intention dans le traitement du diabète de type 2, ce qui en fait, aujourd'hui, le médicament anti-hyperglycémiant le plus prescrit à travers le monde. Malgré cette longue expérience, la metformine garde ses mystères, notamment quant aux mécanismes qui sous-tendent son action antidiabétique et d'autres effets potentiels. Au cours des dernières années, certaines contre-indications à l'utilisation de la metformine ont été, au moins partiellement, levées tandis que de nouvelles indications apparaissent avec, par ailleurs, des perspectives intéressantes dans des domaines aussi importants qu'inattendus, comme le cancer ou les maladies neurodégénératives. Les résultats prometteurs des études animales et des études observationnelles humaines doivent cependant être vérifiés dans des essais d'intervention contrôlés bien conduits.

[Clinical approach of a suspicion of hypoglycaemic malaise in a nondiabetic adult]. / La vignette diagnostique de l'étudiant Mise au point d'une suspicion de malaise hypoglycémique chez une personne adulte non diabétique.

Malaises are often attributed to hypoglycaemia in nondiabetic people who don't have any other serious medical problem. However, such a diagnosis is often overused, because not really demonstrated in most instances. The diagnosis of hypoglycaemia should be structured, based upon the Whipple triad. First, the anamnesis must search for adrenergic and neuroglucopenic symptoms that suggest hypoglycaemia. Afterwards, hypoglycaemia must be authentified by a measurement of a low glucose level at the time of a malaise. Finally, if the malaise is due to a hypoglycaemia, it should resume rapidly after the administration of sugar. When the diagnosis is made based upon this triad, the medical interview should precise the severity of the symptoms and focus on the chronology of the malaises, after meal or in the fasting state, which is crucial to differentiate functional reactice hypoglycaemia from hypoglycaemia due to an insulinoma. Finally, additional medical examinations may be performed, first based upon clinical biology followed, if necessary, by medical imaging. They will not only confirm the diagnosis of hypoglycaemia, but also contribute to find the cause of hypoglycaemia, which will help in choosing the therapeutic strategy.

Résumé : La survenue de malaises est souvent attribuée à une hypoglycémie chez des personnes non diabétiques et, a priori, sans autre problème de santé. Ce diagnostic est, cependant, souvent galvaudé, car habituellement non clairement démontré. Le diagnostic d'hypoglycémie doit se faire de façon structurée en se basant sur la triade de Whipple. Tout d'abord, l'anamnèse doit rechercher les symptômes évocateurs d'hypoglycémie, adrénergiques et neuroglucopéniques. Ensuite, l'hypoglycémie doit être authentifiée par une mesure d'une valeur basse au moment d'un malaise. Enfin, s'il s'agit bien d'une hypoglycémie, le malaise doit disparaître rapidement après resucrage. Une fois le diagnostic posé sur la base de cette triade, l'anamnèse doit faire préciser, outre la sévérité des malaises, leur chronologie, après les repas ou à jeun, ce qui oriente vers une hypoglycémie réactive, fonctionnelle, ou vers une hypoglycémie d'origine organique (insulinome). Des examens complémentaires, faisant d'abord appel à la biologie clinique, ensuite éventuellement à l'imagerie médicale, permettront de, non seulement confirmer le diagnostic d'hypoglycémie, mais aussi d'en préciser l'origine, ce qui orientera la stratégie thérapeutique.

Inhibiting or antagonizing glucagon: making progress in diabetes care.

Absolute or relative hyperglucagonaemia has been recognized for years in all experimental or clinical forms of diabetes. It has been suggested that excess secretion of glucagon by the islet α cells is a direct consequence of intra-islet insulin secretory defects. Recent studies have shown that knockout of the glucagon receptor or administration of a monoclonal specific glucagon receptor antibody make insulin-deficient type 1 diabetic rodents thrive without insulin. These observations suggest that glucagon plays an essential role in the pathophysiology of diabetes and that targeting the α cell and glucagon are innovative approaches in the management of diabetes. Despite active research and identification of promising compounds, no one selective glucagon antagonist is presently used in the treatment of diabetes. Interestingly, besides insulin, several drugs used today in the management of diabetes appear to exert their effects, in part, by inhibiting glucagon secretion (glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors and, possibly, sulphonylureas) or glucagon action (metformin). The potential risks associated with total glucagon suppression include α-cell hyperplasia, increased mass of the pancreas, increased susceptibility to hepatosteatosis and hepatocellular injury and increased risk of hypoglycaemia, and these should be considered in the search and development of new compounds reducing glucagon receptor signalling. More than 40 years after its initial description, hyperglucagonaemia in diabetes can no longer be ignored or minimized, and its correction represents an attractive way to improve diabetes management.

Early milestones in glucagon research.

As an introduction to the Symposium, we have reviewed the early steps in glucagon research from its discovery in 1923 to the establishment of the basics of the physiology and pathophysiology of the hormone after the description of a sensitive and specific radioimmunoassay by Unger and his co-workers in 1959.

[Cardiovascular prevention: could the polypill reduce the risk of clinical inertia and poor compliance?]. / Prévention cardio-vasculaire: la "polypill", une solution pour vaincre l'inertie clinique et le manque d'observance?

The concept of "polypill" for cardiovascular prevention was introduced in 2003 in a landmark paper of the British Medical Journal. A model based on results provided by evidence-based medicine suggested that a "polypill", that contains a statin, three blood pressure lowering drugs (each at half standard dose), aspirin and folic acid, would result in an 80% reduction in the incidence of coronary and cerebrovascular events, while being associated with a good tolerance profile and offering a favourable cost-effectiveness ratio. The present paper aims at presenting the new advances dealing with this new paradigm in cardiovascular prevention. We will present the progresses of the "polypill" concept since 2003, the results of a first controlled clinical trial, the pharmaceutical feasibility for routine clinical use and the potential pharmaco-economical impacts of such a strategy. The "polypill" may offer a solution to avoid physician's clinical inertia and reduce patients's lack of compliance, two drawbacks in the field of cardiovascular prevention.

[Insulin glargine and cancer: a storm in a glass of water?]. / Insuline glargine et cancer: une tempête dans un verre d'eau?

Insulin glargine is widely used as basal insulin in the treatment of type 1 and type 2 diabetes mellitus. However, this insulin analogue has been recently suspected to be associated with an increased risk of cancer, especially breast cancer, in patients with type 2 diabetes. The present article aims at briefly presenting the state of the art based upon currently available data. We will first summarize the observations reported in recent publications, then we will present a critical analysis of these in fact non-conclusive findings, and finally we will conclude with some practical recommendations.

[United Kingdom Prospective Diabetes Study (UKPDS): 10 years later]. / L'étude clinique du mois. "United Kingdom Prospective Diabetes Study": 10 ans plus tard.

A 10-year post-trial monitoring of patients with newly diagnosed type 2 diabetes randomised in the "United Kingdom Prospective Diabetes Study" (UKPDS) demonstrated a continued reduction in microvascular risk (-24%, p = 0.001) and emergent risk reductions for myocardial infarction (-15%, p = 0.01) and death from any cause (-13%, p = 0.007), despite an early loss of glycaemic differences ("legacy effect"). A continued benefit after metformin therapy was evident during the ten-year post-trial follow-up among overweight patients (-33%, p = 0.005 for myocardial infarction and -27%, p = 0.002 for death from any cause). In contrast, the benefits of previously improved blood pressure control were not sustained when between-groups differences in blood pressure were lost during follow-up, except for a reduced risk for peripheral vascular disease. These observations are strong arguments in favour of an early optimisation of blood glucose control and of a sustained control of blood pressure in patients with type 2 diabetes.

[Brain, a gluco-dependent organ: toxic effects of hypoglycaemia and hyperglycaemia]. / Le cerveau, un organe gluco-dépendant. Effets délétères de l'hypoglycémie et de l'hyperglycémie.

Glucose is almost the only energy substrate for the brain. Such glucose dependence explains why any large variation of plasma glucose levels could lead to cerebral dysfunction, which may be severe and progress to a coma. Hypoglycaemic coma, the most common one, has a pure metabolic origin (neuroglucopenia) whereas hyperglycaemic coma is more complex and mainly due to osmotic disturbances. Besides acute changes of plasma glucose concentrations, it is generally recognized that more subtle chronic or recurrent glucose abnormalities could also result in brain dysfunction. However, such clinical consequences are more difficult to assess in clinical practice. Nevertheless, learning perturbations in young patients with type 1 diabetes and memory losses, sometimes severe and subject to progress to dementia ("diabetic encephalopathy") in older type 1 or type 2 diabetic patients, have been reported, although with some controversy. The present paper summarizes the current knowledge of both acute and chronic cerebral dysfunctions following perturbations of blood glucose levels in diabetic patients.

[How to explore...the metabolic syndrome by its new IDF definition]. / Comment j'explore...le syndrome métabolique par sa nouvelle définition dite de "consensus".

The International Diabetes Federation recently proposed a so-called consensus definition of metabolic syndrome. According to this new definition, a subject has the metabolic syndrome if he/she has abdominal obesity (considered as a prerequisite and assessed, in the European population, by a waist circumference > 80 cm in women and > 94 cm in men) and, in addition, at least two other risk factors among 1) elevated fasting triglycerides > or = 150 mg/dl; 2) low HDL cholesterol HDL < 50 mg/dl in women and < 40 mg/dl in men; 3) increased arterial blood pressure > or = 130/ 85 mm Hg; and 4) elevated fasting plasma glucose concentration > or = 100 mg/dl. We will discuss the advantages and limitations of this new definition as well as the consequences of its use on the prevalence of the metabolic syndrome in the Belgian population.

[Proactive study: secondary cardiovascular prevention with pioglitazione in type 2 diabetic patients]. / L'etude Proactive: prévention secondaire des accidents cardio-vasculaires par la pioglitazone chez le patient diabétique de type 2.

PROactive is a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. Patients were assigned to oral pioglitazone titrated from 15 mg to 45 mg or matching placebo, to be taken in addition to their glucose-lowering drugs and other medications. After a mean follow up of 34.5 months, pioglitazone reduced the composite of all-cause mortality, non-fatal myocardial infarction, and stroke (intention to treat analysis: hazard ratio = 0.84; 95% CI: 0.72-0.98; p = 0.027). Various favourable metabolic effects could contribute to this cardiovascular protection, i.e. an absolute 0.5 % reduction in HbA1c, a 9% increase in HDL cholesterol, a 13% decline of triglycerides, and a 3 mm Hg reduction in systolic blood pressure in the pioglitazone group compared to placebo. The requirement of insulin was reduced by almost 50% in the pioglitazone group as compared to the placebo group. The incidence of cases of oedema and congestive heart failure was higher in the pioglitazone group. In conclusion, in patients with type 2 diabetes who are at high cardiovascular risk, pioglitazone improves cardiovascular outcome, and reduces the need to add insulin to glucose-lowering regimens compared to placebo.

[Another look at the implications of the DCCT study]. / Un autre regard sur les implications de l'étude DCCT.

The fundamental role of good metabolic control has been demonstrated in type 1 and type 2 diabetes. Nevertheless, clinicians often wonder why some patients under good metabolic control develop complications while others remain free of such complications, despite a poorly controlled disease. The present study revisited material from the DCCT database, by classifying the 1441 patients as being under good or poor metabolic control if their HbA1c mean level fell in the lower (HbA1c<=6.9%) or upper (HbA1c>/=9.5%) quintile of the overall distribution of mean HbA1c levels observed in the DCCT population. The impact of metabolic control and of other potential factors related to the patient and his/her disease on the development and/or deterioration of complications, in particular diabetic retinopathy and nephropathy, was assessed. Although metabolic control is the major determinant of the risk of developing diabetic retinopathy and nephropathy, the study also emphasizes the significant role of other risk factors, in particularly BMI, disease duration, micro-albuminuria, HbA1c at baseline, gender and age on such complications. It is concluded that early control of the metabolic and clinical status of diabetic patients has major consequences on the evolution of the disease. Nomograms have been proposed to help the clinician in this task.

The kallikrein-kinin system, angiotensin converting enzyme inhibitors and insulin sensitivity.

The therapeutic use of angiotensin converting enzyme (ACE) inhibitors, at a large scale, in arterial hypertension has showed that these molecules can exert beneficial effects on insulin sensitivity and may reduce the occurrence of type 2 diabetes mellitus. One hypothesis explaining these effects of ACE inhibitors may relate to their capacity to interfere with bradykinin (BK) metabolism and action. BK may participate in the regulation of substrate utilization by several tissues by improving blood flow and substrate delivery to the tissues and also by promoting translocation of glucose transporters. Moreover, BK has been shown to increase phosphorylation of insulin receptor and its cell substrates. BK also appears to improve the release of insulin. Furthermore, insulin may activate the kallikrein-kinin system, which consequently may increase its metabolic effects. However, in experimental diabetes mellitus, BK can participate to the inflammatory reaction leading to Langerhans islets destruction. In diabetes, whereas tissue kallikrein mRNA levels were reduced in several organs, an overexpression of kinin receptors, an increase in plasma levels of kininogens and kallikrein and an activation of the kinin system have all been reported. Lastly, kinins may be involved in the development of diabetic nephropathy. Reduction of kinin metabolism by ACE inhibitors might be involved in the beneficial effects exerted by these compounds in diabetic kidney functions.

[Reactive hypoglycaemia, a mysterious, insidious but non dangerous critical phenomenon]. / L'hypoglycémie reactive: un phénomène critique mystérieux, insidieux, mais non dangereux.

Numerous individuals complain of malaise attributed to hypoglycaemia. However, the diagnosis of hypoglycaemia is rarely documented and most often overstated. Reactive hypoglycaemia in the postprandial state is rather exceptional. The diagnosis relies upon the measurement of plasma glucose concentration (< 3 mmol/l or 55 mg/dl) at the time of the malaise. Reactive hypoglycaemia is generally associated with adrenergic symptoms and, less often, with cognitive disturbances. Importantly, a plasma glucose concentration below 3 mmol/l during an oral glucose tolerance test is not sufficient to decide that the patient suffers from reactive hypoglycaemia. Treatment is based on dietary advices including frequent small split meals and limitation of carbohydrates with high glycaemic index. Acarbose, a specific inhibitor of gut alpha-glucosidase enzymes, may be helpful in case of diet failure. As compared with true reactive hypoglycaemia, a postprandial hyperadrenergic reaction without real concomitant hypoglycaemia is much more prevalent. Careful anamnesis may suspect such a diagnosis, but other diagnoses such as panic attack or vasovagal reaction should be excluded. Treatment is purely symptomatic and essentially empiric.

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 cardiovascular diseases using a combined pharmacological approach: is there any place for a "polypill"?]. / Comment je préviens ... les maladies cardio-vasculaires par une approche pharmacologique combinée: y a-t-il place pour une "polypill"?

In the June 28, 2003 issue of the British Medical Journal, an extensive literature survey based on various large meta-analyses of the efficacy and safety of the reduction of four cardiovascular risk factors (cholesterol, arterial blood pressure, platelet aggregation, homocysteine) leads to the conclusion that a combined pharmacological intervention should reduce ischaemic heart disease events by 88% and strokes by 80% in at risk individuals. Therefore, a new paradigm is proposed for the prevention of cardiovascular diseases. This new strategy would consist in the systematic prescription to people with a history of heart attack or stroke, those with any form of obliterative atherosclerotic vascular disease or diabetes, and everyone aged 55 and older of a fixed combination of 6 pharmacological agents independently of initial risk factor profile.... Such pharmacological formulation, called "polypill", should contain a statin, three blood pressure lowering drugs (each at half standard dose), aspirin (75 mg/day) and folic acid (0.8 mg/day). We discuss the pros and cons of this new paradigm. However, the efficacy of such "polypill" remains to be demonstrated in a large controlled clinical trial as well as its superiority as compared to a classical approach of cardiovascular prevention based upon the individual optimal correction of each risk factor thanks a dose titration of each pharmacological compound.

Factors predictive of nephropathy in DCCT Type 1 diabetic patients with good or poor metabolic control.

AIMS: The study aim was to assess the time-related risk of developing diabetic nephropathy [albumin excretion rate (AER) > or =40 mg/24 h] from baseline covariates in Type 1 diabetic patients with either good or poor metabolic control (MC). METHODS: Based on material from the Diabetes Control and Complications Trial study (n=1441), patients were considered as under good or poor MC if their HbA1c mean level up to last visit fell in the lowest (< or =6.9%) or highest (>or =9.5%) quintile of the overall HbA1c distribution, respectively. Prevalence cases of nephropathy were excluded from the study. Survival analysis and Cox regression were applied to the data. RESULTS: Among patients with good MC (n=277), 15% had developed nephropathy at the end of the study. Conversely, among patients with poor MC (n=268), the proportion without the complication was 52%. When adjusting for MC, time to diabetic nephropathy was related to age (P<0.0001), AER (P<0.001), duration of diabetes (P<0.005), body mass index (BMI) (P<0.005), all at baseline, and to gender (P<0.01). Patients with upper normal range AER levels, longer duration of diabetes and lower BMI were at higher risk, regardless of MC. The adverse effect of younger age on diabetic nephropathy was more marked in good than in poor MC. Although women tended to develop the complication more often under good MC, they appeared to be better protected under poor MC. CONCLUSIONS: This study confirms occurrence of diabetic nephropathy under good MC and non-occurrence of the complication despite poor MC. It also demonstrates that some baseline covariates can affect, in a differential manner, time to diabetic nephropathy depending on MC.

[Postprandial hyperglycemia. I. Physiopathology, clinical consequences and dietary management]. / L'hyperglycémie post-prandiale. I. Physiopathologie, conséquences cliniques et approaches diététiques.

Postprandial hyperglycaemia depends on the amount and type of ingested carbohydrates and/or the degree of inhibition of hepatic glucose output following a meal. The kinetics of carbohydrate absorption is directly influenced by the type of food (carbohydrates with variable glycaemic indices, fibre content of the meal) and by the speed of gastric emptying. Hepatic glucose output is remarkably inhibited by insulin and strongly stimulated by glucagon. It remains abnormally high after a meal in diabetic patients because of insufficient portal insulin concentrations, hepatic insulin resistance and/or hyperglucagonaemia. In diabetic patients, postprandial hyperglycaemia contributes to the aggravation of chronic hyperglycaemia, and thus to the increase of glycated haemoglobin levels. Furthermore, it has been recently demonstrated that postprandial hyperglycaemia increases the cardiovascular risk, even in nondiabetic subjects, probably by inducing endothelial dysfunction. Appropriate dietary counselling plays a key-role in the control of postprandial hyperglycaemia. Generally speaking, it includes a selection of carbohydrates with low glycaemic index and a higher fibre intake. Pharmacological interventions may also be considered when necessary.

Changes in blood glucose and plasma insulin levels induced by bradykinin in anaesthetized rats.

1. The influence of bradykinin (BK) on blood glucose and plasma insulin levels was investigated in anaesthetized rats. 2. Blood glucose level was dose-dependently increased by intravenous infusion of BK. This effect of BK was enhanced by captopril, an inhibitor of angiotensin-converting enzyme (ACE). Des-Arg9-bradykinin (DABK), a kinin B1 receptor agonist, did not modify blood glucose levels while the effect of BK was inhibited by Hoe-140, a kinin B2 receptor antagonist. 3. The effect of BK was reduced by the NO-synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), and by the cyclo-oxygenase inhibitor, indomethacin. The effect of BK was suppressed by the association of propranolol with phentolamine or phenoxybenzamine. It was also reduced by hexamethonium, a ganglion-blocking drug. In adrenalectomized rats, the infusion of BK slightly decreased blood glucose levels. 4. The hyperglycaemic effect of adrenaline was suppressed by propranolol associated with phentolamine or phenoxybenzamine, but it was not modified by L-NAME. 5. Infusion of BK did not modify plasma insulin levels. However, after phentolamine and propranolol, BK induced a transient 2 fold rise in plasma insulin levels. The release of insulin was dose-dependent and inhibited by Hoe-140. 6. We conclude that infusion of BK induces, via a stimulation of B2 receptors, the release of NO and of prostanoids. The latter agents activate through a reflex pathway the release of catecholamines from the adrenal medulla. This release increases blood glucose levels and reduces plasma insulin levels. After adrenoceptor inhibition, BK induces a secretion of insulin, via the stimulation of B2 receptors.