[Smoking, obesity and diabetes: a clinically important interaction]. / Tabagisme, obésité et diabète: une interaction cliniquement importante.

Smoking, obesity and diabetes are among the leading cause of premature death worldwide. Smokers have globally a lower body weight compared with non smokers but they tend to accumulate more fat in the abdomen. Most smokers gain weight when they quit smoking, however this does not seem to diminish the health benefits associated with smoking cessation. Smoking increases the risk of developing type 2 diabetes. Among people with diabetes, smoking significantly increases the risks of complications and mortality. Interventions with pharmacologic help should be offered to all smokers, with or without diabetes, in order to increase smoking cessation rates and limit weight gain.

[What Policy for the Management of Smoking During Pregnancy? - CNGOF-SFT Expert Report and Guidelines on the management for Smoking Management During Pregnancy]. / Quelle politique de prise en charge du tabagisme pendant la grossesse ? ­ Rapport d'experts et recommandations CNGOF-SFT sur la prise en charge du tabagisme en cours de grossesse.

Smoking during pregnancy is a public health problem. Individual screening is carried out in France during pregnancy consultations, followed by non-systemic care (with or without nicotine replacement therapy). In the UK, pregnant smokers are routinely screened during pregnancy follow-up and then referred to smoking cessation services. In order to improve their adherence, and smoking cessation, patients can be contacted, in particular by phone. We therefore recommend to systematically screen for smoking during pregnancy by asking the question of smoking or by measuring the CO exhaled during the various consultations, to offer care in collaboration with a local smoking cessation service and renew the requests if necessary. We need to develop these care networks in France.

[CNGOF-SFT Expert Report and Guidelines for Smoking Management during Pregnancy-Short Text]. / Rapport d'experts et recommandations CNGOF-SFT sur la prise en charge du tabagisme en cours de grossesse­texte court.

OBJECTIVES: To provide up-to-date evidence-based guidelines for the management of smoking cessation during pregnancy. METHODS: Systematic review of the international literature. We identified papers published between January 2003 and April 2019 in Cochrane PubMed, and Embase databases with predefined keywords. All reports published in French and English relevant to the areas of focus were included and classified according the level of evidence ranging from 1 (highest) to 4 (lowest). The strength of the recommendations was classified according to the Haute Autorité de santé, France (ranging from A, highest to C, lowest). RESULTS: "Counseling", involving globally all kind of non-pharmacological interventions, has a modest benefit on smoking cessation, birth weight and prematurity. Moderate physical activity did not show a significant effect on smoking cessation. The systematic use of feedback by measuring the expired air carbon monoxide concentration do not influence smoking abstinence but it may be used in establishing a therapeutic alliance. The use of self-help interventions and health education are recommended in helping pregnant smokers quit. The prescription of nicotine replacement therapies (NRT) may be offered to any pregnant woman who has failed stopping smoking without medication This prescription can be initiated by the health care professional taking care of the pregnant woman in early pregnancy. There is no scientific evidence to propose the electronic cigarette for smoking cessation to pregnant smokers; it is recommended to provide the same advice and to use methods that have already been evaluated. The use of waterpipe (shisha/narghile) during pregnancy is associated with decreased fetal growth. It is recommended not to use waterpipe during pregnancy. Breastfeeding is possible in smokers, but less often initiated by them. Although its benefit for the child's development is not demonstrated to date, breastfeeding allows the mother to reduce or stop smoking. The risk of postpartum relapse is high (up to 82% at 1 year). The main factors associated with postpartum abstinence are breastfeeding, not having a smoker at home, and having no symptoms of postpartum depression. CONCLUSIONS: Smoking during pregnancy concerns more than hundred thousand women and their children per year in France. It is a major public health burden. Health care professionals should be mobilized for reducing or even eradicating it.

Smoking and smoking cessation in pregnancy. Synthesis of a systematic review.

OBJECTIVES: To provide up-to-date evidence-based guidelines for the management of smoking cessation during pregnancy and the post-partum period. STUDY DESIGN: A systematic review of the international literature was undertaken between January 2003 and April 2019. MEDLINE, EMBASE databases and the Cochrane library were searched for a range of predefined key words. All relevant reports in English and French were classified according to their level of evidence ranging from 1(highest) to 4(lowest). The strength of each recommendation was classified according to the Haute Autorité de Santé (French National Authority for Health) ranging from A (highest) to C (lowest). RESULTS: "Counselling", including all types of non-pharmacological interventions, has a moderate benefit on smoking cessation, birth weight and prematurity. The systematic use of measuring expired air CO concentration does not influence smoking abstinence, however, it may be useful in assessing smoked tobacco exposure prior to and after quitting. The use of self-help therapies and health education are recommended in helping pregnant smokers quit and should be advised by healthcare professionals. Nicotine replacement therapies (NRT) may be prescribed to pregnant women who have failed to stop smoking after trying non-pharmacological interventions. Different modes of delivery and dosages can be used in optimizing their efficacy. Smoking in the postpartum period is essential to consider. The same treatment options as during pregnancy can be used. CONCLUSION: Smoking during pregnancy concerns more than a hundred thousand women each year in France resulting in a major public health burden. Healthcare professionals should be mobilised to employ a range of methods to reduce or even eradicate it.

[Maternal smoking during pregnancy: A risk factor for respiratory disorders in children]. / Tabagisme maternel pendant la grossesse : un facteur de risque des troubles respiratoires de l'enfant après la naissance.

Maternal smoking during pregnancy (MSDP) is a well-established risk factor for negative pregnancy outcomes, but its negative effects on the health of the child after birth are less well known by both health professionals and the general public. Large cohort studies over the past 10 years have shown that MSDP is an independent risk factor for several childhood health problems such as e.g. obesity and smoking. A large number of recent studies and 3 meta-analyses demonstrate that MSDP is an independent risk factor of wheezing and asthma of the child exposed in utero to maternal smoking. MSDP is associated with epigenetic toxicities the currently most plausible hypothesis to explain the diversity of its postnatal negative effects. The eradication of MSDP could contribute to the reduction of health problems in the next generation, including the incidence of childhood respiratory disorders.

Identification of factors associated with impaired hypoglycaemia awareness in patients with type 1 and type 2 diabetes mellitus.

OBJECTIVES: To assess clinical factors associated with impaired hypoglycaemia awareness (HA). METHODS: Survey of 241 type 1 and type 2 diabetic patients hospitalised in a diabetes department for a diabetes education program. Demographic, diabetes and psychiatric characteristics and subjective hypoglycaemic symptoms were recorded by a self-report questionnaire. RESULTS: Age and body mass index (BMI) was greater and glycated haemoglobin was lower in diabetic patients reporting impaired HA, however, these latter differences became not significant when age was included as a covariate. There were significantly more current smokers among those with impaired HA and controlling for age accentuated this difference. Current treatment by insulin was not associated with impaired HA. Backward stepwise logistic regression showed that type 2 diabetic patients were twice as likely to have impaired HA than type 1 diabetic patients (OR = 2.195, 95% CI: 1.017-4.734, P = 0.04). Moreover, higher age, current smoking and type 2 diabetes interacted significantly in increasing the likelihood of impaired HA. Among those with impaired HA more patients experienced drowsiness and nervousness and less patients reported tremor during the hypoglycaemic episodes. No other symptoms were associated with impaired HA. CONCLUSION: Type 2 diabetic patients, whether on insulin or not, and especially if they are of advanced age and if they smoke, are at increased risk of impaired HA.

[Nicotine replacement therapies during pregnancy: what do we know about the balance between benefits and risks?]. / Les traitements substitutifs nicotiniques pendant la grossesse: que sait-on du rapport bénéfice-risque?

Maternal smoking during pregnancy induces obstetrical and fetal complications but also has an impact on newborns, infants, children and adults. Nicotine replacement therapies are authorized during pregnancy in France, the purpose being to reduce fetal exposure to toxic compounds in tobacco smoke. However, it is not proven that nicotine replacement therapy is harmless to the fetus and to date, no study has demonstrated any beneficial effect in terms of abstinence. It is suggested that benefit and risks of nicotine replacement therapies during pregnancy should be evaluated.

Hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients.

Thirty-seven insulin-dependent diabetic patients were tested for symptoms of hypoglycemia, cardiac autonomic neuropathy (i.e., heart rate variation during deep breathing, Valsalva maneuver, immediate heart rate response to standing), and isoproterenol sensitivity (defined as the dose of isoproterenol required to increase heart rate by 25 beats/min: I25). Tests of cardiac autonomic neuropathy showed no relation to hypoglycemic symptoms. On the contrary, a clear relationship could be established between isoproterenol sensitivity and adrenergic symptoms of hypoglycemia. Diabetic patients with decreased response to isoproterenol had fewer adrenergic symptoms, perceived hypoglycemia at a lower blood glucose level, and had more hypoglycemic accidents. Symptoms most related to isoproterenol sensitivity were tremor, sweaty palms, and hunger. With the isoproterenol-sensitivity test a distinction could be made between the groups at high (I25 greater than 3 micrograms) and low (I25 less than 3 micrograms) risk for hypoglycemic accidents. We suggest that the isoproterenol-sensitivity test could be used to identify diabetic patients at increased risk for hypoglycemia.

Phobic symptoms, particularly the fear of blood and injury, are associated with poor glycemic control in type I diabetic adults.

OBJECTIVE: To investigate the presence of psychiatric disorders and symptoms in type I diabetic patients and to identify those that may influence metabolic control as assessed by GHb levels. RESEARCH DESIGN AND METHODS: This was a cross-sectional study. One hundred and two consecutive patients with type I diabetes who were regular outpatient visitors of a diabetology department were evaluated. The psychiatric assessments included self-rating questionnaires (General Health Questionnaire and Fear Questionnaire) and observer-rating questionnaires (Montgomery-Asberg Depression Rating Scale [MADRS] and Mini International Interview). Diabetic characteristics were assessed by a structured interview. The observer was blind to the diabetic characteristics of the patients. RESULTS: Type I diabetic patients with GHb levels > or = 8% had higher psychological distress, scored significantly higher for symptoms of agoraphobia and for fear of blood and injury, had substantially higher levels of anxiety-depression, and performed significantly fewer blood glucose measurements per day. They did not differ in MADRS score from patients with GHb levels < 8%. Multivariate analysis showed that GHb was positively associated with the total score of phobic symptoms and the level of anxiety-depression and inversely associated with the number of daily blood glucose measurements. These factors explained 41% of the variance of GHb. The inverse relationship between GHb and the number of blood glucose measurements per day was mainly influenced by the fear of blood and injury. Patients with high scores for the fear of blood and injury performed fewer blood glucose measurements and had poorer glycemic control; conversely, subjects without fear of blood and injury performed more daily blood glucose measurements and had better glycemic control. CONCLUSIONS: Phobic symptoms are frequent in patients with type I diabetes. The intensity of phobic symptoms and anxiety-depression negatively influences metabolic control. Increased fear of blood and injury may lead some patients to perform few home blood glucose measurements and may result in poorer glycemic control. This suggests that, by decreasing the fear of blood, injury, and injection, metabolic control may be improved.

[Electronic cigarettes: A therapeutic tool, a social phenomenon or a business?]. / La cigarette électronique : outil thérapeutique, phénomène social ou business ?

Smoking is the first avoidable cause of morbidity and mortality. It is estimated that there were around 14 million smokers in France in 2012 and that smoking results in 70,000 deaths per year. All types of interventions reducing with efficacy the incidence and prevalence of smoking are to consider in prolonging life expectancy. Electronic cigarettes (e.cig.) are a social phenomenon but they also are a system delivering pharmacologically active substances; their use concerns today several millions of individuals in France. By this fact, it became important for clinical practitioners to acquire some knowledge about e. cig. Most of the e.cig. contains nicotine, thus, e.cig. are now called in the medical literature as electronic nicotine delivery system (ENDS). It is highly plausible that ENDS, which are, as of today, consumer products and not health products, deliver nicotine with a good bioavailability and could, if largely used, help to reduce smoking prevalence. However, because of current lack of regulations, as of today, the risk/benefit ratio of ENDS as an aid to help smokers quit and their adverse effect profile cannot be established. It is of public health responsibility to promote evidence based knowledge about e.cig. to know with confidence their risk/benefit ratio.

Decreased beta-adrenergic sensitivity in insulin-dependent diabetic subjects.

To study beta-adrenergic sensitivity in diabetes mellitus, we performed isoproterenol sensitivity tests in 34 insulin-dependent diabetic patients and 10 age-matched normal subjects. beta-adrenergic sensitivity [defined as the dose of isoproterenol required to increase the resting heart rate by 25 beat/min, (I25)] was significantly higher in the diabetic group (4.07 +/- 1.4 micrograms, mean +/- SD) than in the normal group (2.02 +/- 1.49 micrograms). A comparison of I25 of normal subjects and diabetic patients as a function of age showed that the latter were significantly less sensitive to beta-adrenergic stimulation at all ages (P less than 0.01). In diabetic patients, beta-adrenergic sensitivity also increased with the duration of diabetes (r = 0.64, P less than 0.0005), but the correlation was stronger when the age of the patients and the duration of the diabetes were both taken into consideration (r = 0.72, P less than 0.0005). We conclude that beta-adrenergic sensitivity is diminished in patients with type I diabetes mellitus of all ages.

Suspected postprandial hypoglycemia is associated with beta-adrenergic hypersensitivity and emotional distress.

Suspected postprandial (reactive or idiopathic) hypoglycemia is characterized by predominantly adrenergic symptoms appearing after meals rich in carbohydrates and by their rare association with low blood glucose level (< 2.77 mmol/L). We studied heart rate, blood pressure, plasma insulin, C-peptide, and catecholamine responses during a 5-h oral glucose tolerance test in eight patients with suspected postprandial hypoglycemia and eight age-, sex-, and body mass index-matched healthy controls. We also evaluated beta-adrenergic sensitivity by using the isoproterenol sensitivity test. Psychological profile was assessed by the Symptom Checklist (SCL-90R) self-report symptom inventory. Patients with suspected postprandial hypoglycemia had higher beta-adrenergic sensitivity (defined as the dose of isoproterenol required to increase the resting heart rate by 25 beats/min) than controls (mean +/- SEM, 0.8 +/- 0.13 vs. 1.86 +/- 0.25 microgram isoproterenol; P = 0.002). After administration of glucose (75 g) blood glucose, plasma C-peptide, plasma epinephrine, and plasma norepinephrine responses were identical in the two groups, but plasma insulin was higher in the patients (group effect, P = 0.02; group by time interaction, P = 0.0001). Both heart rate and systolic blood pressure were significantly higher (but remained in the normal range) after glucose administration in patients with suspected postprandial hypoglycemia than in controls (group by time interactions, P = 0.004 and 0.0007, respectively). After glucose intake, seven patients had symptoms (palpitations, headache, tremor, generalized sweating, hunger, dizziness, sweating of the palms, flush, nausea, and fatigue), whereas in the control group, one subject reported flush and another palpitations, tremor, and hunger. Analysis of the SCL-90R questionnaire revealed that patients had emotional distress and significantly higher anxiety, somatization, depression, and obsessive-compulsive scores than controls. We may conclude that patients with suspected postprandial hypoglycemia have normal glucose tolerance, increased beta-adrenergic sensitivity, and emotional distress.

Lack of hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients.

Plasma epinephrine, norepinephrine, and dopamine responses were studied in insulin-dependent diabetic patients at rest, on standing and during insulin-induced hypoglycemia. beta-Adrenergic sensitivity was evaluated by the isoproterenol sensitivity test. Five men who had adrenergic symptoms during hypoglycemia and no severe hypoglycemic accidents (coma, seizures) (group A) and five men who had repeated severe hypoglycemic accidents but lack of adrenergic symptoms of hypoglycemia (group B) were studied. The mean resting plasma epinephrine was lower in group B (147 +/- 22 pmol/L, SEM) than in group A (398 +/- 98 pmol/L, P less than 0.02). On standing plasma epinephrine increased significantly in both groups. During hypoglycemia blood glucose decreased identically in the two groups; plasma epinephrine and norepinephrine increased significantly and to the same extent in both groups; the mean maximal heart rate was significantly greater in group A than in group B. Isoproterenol sensitivity (defined as the dose of isoproterenol required to increase heart rate by 25 beats/min) was lower in group B (5.87 +/- 1.12 micrograms) than in group A (2.37 +/- 0.22 micrograms, P less than 0.01). The group B patients had significantly fewer hypoglycemic symptoms during insulin-induced hypoglycemia than did group A patients. We conclude that decreased beta-adrenergic sensitivity contributes to the lack of adrenergic symptoms of hypoglycemia in insulin-dependent diabetic patients.

Monoamine oxidase A and B activities in heavy smokers.

There is a strong association between depression and smoking. Because monoamine oxidase (MAO) inhibition leads to antidepressant effect and in vitro studies have shown that cigarette smoke inhibits MAO activity, it is conceivable that smoking may have an antidepressant effect, if smokers have reduced MAO activity. Therefore, we assessed platelet MAO-B activity and plasma concentration of catecholamine metabolites reflecting MAO-A activity in heavy dependent smokers and nonsmokers matched for sociodemographic characteristics. Platelet MAO-B activity, plasma 3,4-dihydroxyphenylglycol, plasma 3,4-dihydroxyphenylacetic acid, and plasma 3,4-dihydroxyphenylalanine concentrations were significantly lower in smokers than in nonsmokers, whereas plasma norepinephrine did not differ. Significantly more smokers reported previous history of depression, manic episode, panic attack, agoraphobia, and simple phobia. Smokers had higher scores (p < 0.001) on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Scales. It is concluded that the activities of both forms of the MAO are reduced in heavy dependent smokers.

Determination and comparison of the pressor effect of tyramine during long-term moclobemide and tranylcypromine treatment in healthy volunteers.

Monoamine oxidase inhibitors can elicit increases in systolic blood pressure after tyramine ingestion (cheese effect). Moclobemide is a new, reversible, preferential monoamine oxidase A inhibitor with antidepressant properties. Its potentiation of the tyramine pressor effect during 200 mg t.i.d. chronic treatment was compared with tranylcypromine, 10 mg b.i.d., in a double-blind, parallel-group, placebo-controlled study (n = 16). Tyramine was mixed with food and ingested in increasing daily doses, during a normal meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (tyramine 30). When compared with the usual fasting oral tyramine tests performed in the same subjects, the mean tyramine 30 dose with a meal was 2.8 times higher. The mean tyramine 30 dose with a meal decreased from 1450 mg (range, 800 to 2000 mg) during placebo to 306 mg (range, 150 to 500 mg) during moclobemide (factor, 5.0) and from 1200 mg (range, 1000 to 1600 mg) during placebo to 35 mg (range, 20 to 50 mg) during tranylcypromine (factor, 38.2). The duration of the systolic blood pressure increase was longer with tranylcypromine (126 minutes) than with moclobemide (69 minutes) (p less than 0.01).

A single dose of three different ophthalmic beta-blockers antagonizes the chronotropic effect of isoproterenol in healthy volunteers.

The systemic effect of three beta-blocking eyedrops was compared in a placebo-controlled, double-blind trial in 12 healthy male volunteers. Each subject received successively each treatment in random order at weekly intervals. The eyedrops administered were as follows: 0.5% timolol, 2% carteolol, 0.6% metipranolol, and placebo. We evaluated the intraocular pressure and systemic beta-blockade 3 hours after a single administration of one eyedrop in each eye. The systemic beta-blocking effect was evaluated by the isoproterenol sensitivity test, that is the dose of isoproterenol required to increase resting heart rate by 25 bpm (I25). Each beta-blocking eyedrop antagonized the chronotropic effect of isoproterenol. I25 for placebo was 3.1 +/- 0.5 micrograms, for metipranolol 5.2 +/- 0.9 micrograms (P less than 0.005), for timolol 10.9 +/- 1.9 micrograms (P less than 0.001), and for carteolol 39.6 +/- 5.4 micrograms (P less than 0.0005). Each treatment significantly decreased the intraocular pressure: metipranolol 3.6 +/- 0.4 mm Hg (P less than 0.001), timolol 2.44 +/- 0.4 mm Hg (P less than 0.01), and carteolol 2.38 +/- 0.48 mm Hg (P less than 0.01) compared with placebo. The resting heart rate and blood pressure were not influenced by the treatments. Even though the results might be different in the case of an earlier or a later time of evaluation or chronic administration, we believe that the isoproterenol sensitivity test may be used to evaluate the systemic effect of beta-blocking eyedrops.

Blunted 5-HT1A-receptor agonist-induced corticotropin and cortisol responses after long-term ipsapirone and fluoxetine administration to healthy subjects.

OBJECTIVES: To assess whether acute 5-hydroxytryptamine-1A (5-HT1A)-receptor-mediated corticotropin, cortisol, and temperature responses are maintained after 3 weeks of treatment with controlled-release (CR) ipsapirone and fluoxetine compared with placebo and whether changes are reversible after cessation of treatment. METHODS: This was a randomized parallel-group study. Ten healthy subjects received ipsapirone CR or fluoxetine, and eight received placebo in a double-blind manner. An ipsapirone challenge test with 20 mg ipsapirone immediate-release formulation (IR) was performed before treatment (day 0) and after 20 days of treatment with placebo, 80 mg/day ipsapirone CR, or 20 mg/day fluoxetine (day 21). From day 22 to day 34 all subjects received placebo in a simple-blind manner. A third ipsapirone challenge test was performed on day 35. RESULTS: Before treatment, resting plasma corticotropin and cortisol concentrations and increases in plasma corticotropin and cortisol concentrations after challenge with 20 mg ipsapirone IR were similar for the three groups. After 20 days of treatment, plasma corticotropin and cortisol concentrations were similar before challenge, but ipsapirone IR-induced increases in plasma corticotropin and cortisol concentrations were significantly lower in both the ipsapirone CR group (corticotropin, 6.5 +/- 2 pg/ml; cortisol, 1.5 +/- 0.7 micrograms/dl) and fluoxetine group (corticotropin 4.4 +/- 2 pg/ml; cortisol 1.5 +/- 0.7 micrograms/dl) compared with placebo (corticotropin, 34 +/- 14 pg/ml; cortisol, 5.8 +/- 2 micrograms/dl, mean +/- SEM). After 2 weeks of placebo administration, plasma corticotropin and cortisol responses to ipsapirone IR again became identical in all three groups. Plasma ipsapirone concentrations were similar in all groups during each challenge. The hypothermic response to ipsapirone IR showed no difference before treatment, at the end of the treatment period, or 2 weeks after cessation of treatment. Long-term administration of antidepressants to the healthy subjects did not lead to any serious adverse effects. CONCLUSIONS: Long-term administration of fluoxetine and ipsapirone did not influence resting plasma corticotropin and cortisol concentrations in the morning. Stimulation of corticotropin and cortisol release by a selective 5-HT1A-agonist is reduced with long-term administration of these serotoninergic antidepressants. This subsensitivity of postsynaptic 5-HT1A-receptors is reversible.

Reduction of hyperglycemia after oral glucose load by the new alpha 2-adrenergic receptor antagonist SL 84.0418 in healthy subjects.

OBJECTIVE: To assess the antihyperglycemic activity of a new peripherally acting alpha 2-adrenergic receptor antagonist, SL 84.0418 in healthy volunteers METHODS: This was a randomized, double-blind crossover study. The effects of 10, 50, and 100 mg SL 84.0418 on blood glucose, plasma insulin, C-peptide, glucagon, epinephrine, and norepinephrine were investigated in comparison with placebo and 5 mg glipizide before and after an oral glucose challenge (75 gm). RESULTS: Peak blood glucose and area under the blood-glucose curve were dose-dependently reduced by SL 84.0418; the extent of this reduction was similar with 100 mg SL 84.0418 and glipizide. Glipizide but not SL 84.0418 decreased nadir blood glucose. Plasma insulin and C-peptide were increased by glipizide but not by SL 84.0418. Treatments did not modify plasma glucagon. Plasma epinephrine increased during glipizide treatment and plasma norepinephrine increased during treatment with 50 and 100 mg SL 84.0418. Systolic and diastolic blood pressure were moderately enhanced by 50 and 100 mg SL 84.0418. Adverse effects reflecting alpha 2-adrenergic receptor blockade occurred more frequently with 100 mg SL 84.0418. The adverse effect profile of 50 mg SL 84.0418 was not different from that observed with glipizide. CONCLUSION: The alpha 2-adrenergic receptor antagonist SL 84.0418 dose dependently reduced the increase in blood glucose after glucose load without modification of plasma insulin. It may represent an alternative to sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus. Further studies are needed to assess its efficacy and tolerability in non-insulin-dependent patients.