[The new insulins]. / Les nouvelles insulines.

The discovery and the use of insulin more than 80 years ago is considered one of the greatest medical breakthroughs of the 20th century. Very rapid progresses led to disposition of very pure and human insulins with different pharmacokinetic profiles. Nevertheless the pharmacokinetics of those conventional rapid and long acting insulin where very far away from the physiological pattern of insulin secretion. It is thus very difficult, using those conventional insulins to obtain a good metabolic control without a very high risk of hypoglycemia. To obtain a good metabolic control and to limit frequent hypoglycemia is essential, on one hand to avoid the apparition and evolution of micro and macroangiopatic complications as well for type 1 as for type 2 diabetic patients, and, on the on the other hand to allow good quality of life for people with diabetes. The use of rapid acting analogues lispro, aspart and glulisine (quicker and shorter action when compared to classical rapid acting insulin) and of long acting analogues glargine and detemir (pharmacokinetic profile without peak of action and very low intra subject coefficient of variability) allowed to reach more easily a good metabolic control with a low risk of hypoglycemia. Progresses are of course still needed to ameliorate the situation of insulin treated diabetic people.

[The role of diabetes associations]. / Le rôle des associations du diabète.

The first diabetes association was created in 1926, soon after the first clinical use of insulin, in Portugal. In Belgium, the "Association Belge du Diabète" was founded in 1942, and the International Diabetes Federation (IDF) was created in 1950 with at that time 16 associations, in 2005 more than 180 associations. The aims of these associations are: --Defence of the rights of the diabetic people in all fields, --Education of the patients and their family as well as of the healthcare professionals on diabetes, --Representation of people with diabetes and of healthcare professionals involved in diabetes at all levels, keeping in mind the major importance of solidarity, --Support to the clinical as well as the fundamental research, --Increase of the global knowledge concerning diabetes, --Actions to favour positive changes, --Act as the global advocate of the cause of diabetes --Facilitate the access to medication (especially insulin), which still is a major problem in many parts of the world, Knowing the explosion of diabetes throughout the world with all the medical, economical, professional, social and human problems related to this major increase, it is obvious that the role of diabetes associations still is and will be even more and more important.

[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.

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.

Risk of developing retinopathy in Diabetes Control and Complications Trial type 1 diabetic patients with good or poor metabolic control.

OBJECTIVE: The study goal was to assess and predict the risk of developing retinopathy in type 1 diabetic patients with extreme metabolic control. RESEARCH DESIGN AND METHODS: Based on material from the Diabetes Control and Complications Trial (DCCT) study (n = 1,441 patients), patients without retinopathy at baseline (DCCT primary cohort) were considered under good or poor metabolic control if the mean HbA(1c) level (until the last visit) fell in the lower or upper 20% of the overall HbA(1c) distribution, respectively. Retinopathy was recorded as either absent or present. Logistic regression was used to predict retinopathy from covariates used in the DCCT retinopathy study. RESULTS: Among the 153 DCCT patients with "good metabolic control" (mean HbA(1c) < or = 6.87%), three-step change retinopathy developed in 15 (9.8%), and 138 (90%) remained free of retinopathy. Conversely, among the 166 patients with "poor metabolic control" (mean HbA(1c) > or = 9.49%), the complication did not develop in 71 (43%) and did develop in 95 (57%). Whereas occurrence of diabetic retinopathy was primarily due to metabolic control (P < 0.0001) and duration of participation in the study (P < 0.0001), two other covariates were found to be significant prognostic factors of the complication: HbA(1c) at baseline (OR 1.37, P < 0.001) and BMI (OR 1.11, P < 0.05). CONCLUSIONS: This study confirms that retinopathy develops in approximately 10% of patients with type 1 diabetes under good metabolic control, whereas > 40% of patients with type 1 diabetes remain free of retinopathy despite poor metabolic control. After adjusting for metabolic control and duration of participation in the study, it was found that previous glycemic exposure (HbA(1c)) and BMI may provide a possible explanation to such paradoxical clinical situations.

High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry.

OBJECTIVE: To study the presence and levels of GAD65 antibodies (GADA), IA-2 antibodies (IA-2-A), and islet cell antibodies (ICA) during the first years after clinical onset of type 1 diabetes in relation to age at diagnosis. RESEARCH DESIGN AND METHODS: Type 1 diabetic patients (n = 194) <40 years of age were consecutively recruited at the time of diagnosis by the Belgian Diabetes Registry and followed during the first 4 years of insulin treatment. ICA were determined by indirect immunofluorescence assay and IA-2-A, GADA, and insulin autoantibodies by a radioligand assay. RESULTS: Overall, 94% of initially antibody-positive patients (n = 180) remained positive for at least 1 antibody type 4 years after diagnosis. In the case of diagnosis after 7 years of age, GADA, IA-2-A, and ICA persisted in 91, 88, and 71%, respectively, of the initially antibody-positive patients. Antibody persistence was lower in those diagnosed at <7 years of age, amounting to 60% for GADA, 71% for IA-2-A, and 39% for ICA. In 57% of the initially antibody-positive patients, at least 1 type of autoantibody reached peak values after diagnosis. This occurred more frequently for clinical onset after 7 years of age and more often for GADA (49%) than for IA-2-A (29%) or ICA (19%). Of the patients, 24% that were negative for GADA at onset became GADA-positive during the following 4 years. Among the 7% initially antibody-negative patients, 2 of 14 subjects developed antibodies after clinical onset. CONCLUSIONS: In particular, for diagnosis after 7 years of age, islet cell-specific autoantibodies generally persist for many years after diagnosis. There is also a high frequency of increasing antibody levels and of conversion to antibody positivity in the first 4 years after diagnosis and start of insulin treatment. Thus, determination of antibodies at diagnosis can underestimate the number of cases with autoimmune type 1 diabetes, in particular with assays of lower sensitivity. The divergent temporal patterns of ICA, GADA, and IA-2-A suggest that the ICA test recognizes other antibody specificities besides GADA and IA-2-A and reflects other autoimmune processes; it also indicates that GADA assays have a higher diagnostic sensitivity in the period after clinical onset.

Usefulness of fluoxetine in obese non-insulin-dependent diabetics: a multicenter study.

Weight reduction is essential in the management of most non-insulin-dependent diabetics, but this therapeutical goal is difficult to obtain. In this double-blind parallel study, 82 non-insulin-dependent diabetics, moderately obese (BMI = 30 - 39 kg/m2), were given for an 8-week period either placebo (P) or fluoxetine (F), a specific serotonin reuptake inhibitor, in addition to their usual antidiabetic treatment. Thirty-nine of them received 60 mg fluoxetine a day and 43 were given the placebo. At admission, both groups had similar weight excess, metabolic control and serum lipid values. In comparison with the P-treated subjects, those treated with fluoxetine (F) lost more weight after 3 weeks (-1.9 vs. -0.7 kg, p < -0.0009) and after 8 weeks (-3.1 vs. -0.9 kg, p < 0.0007). Fasting blood glucose decreased in group F after 3 weeks (-1.5 vs -0.4 mmol/L, p < 0.003) and after 8 weeks (-1.7 vs. -0.02 mmol/L, p < 0.0004). HbAlc decreased from 8.5% to 7.7% in group F and from 8.6% to 8.3% in group P (p = 0.057). Mean triglyceride level was also reduced in group F after 8 weeks (p = 0.042). Fasting C-peptide did not change in either group, but fasting insulin values decreased in group F after 3 weeks (p < 0.02) and after 8 weeks (p < 0.05). The insulin/C-peptide molar ratio decreased significantly in group F after 3 weeks (p < 0.04) and after 8 weeks (p < 0.05) in comparison with group P. The drug was generally well tolerated and no major side effects were reported. In conclusion, the addition of fluoxetine to the usual oral hypoglycemic agent therapy might be beneficial in obese non-insulin-dependent diabetics, at least on a short-term basis.

Fluoxetine therapy in obese diabetic and glucose intolerant patients.

A double-blind placebo-controlled trial was conducted, involving 97 obese diabetic and glucose intolerant patients receiving either 60 mg fluoxetine daily (47 patients) or a placebo (50 patients); a similar calorie-restricted diet was prescribed to all patients. Weight loss was significantly higher in the fluoxetine-treated patients, whose diabetic status improved. Drop-out rate was not significantly different for both groups of patients.

[Lack of benefit from the intermittent administration of insulin in treatment using subcutaneous perfusion pump in type 1 diabetes]. / Absence de bénéfice de l'administration intermittente de l'insuline lors d'un traitement par pompe a perfusion sous-cutanée chez le diabétique de type-1.

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.

[Peroperative localization of insuloma using staged portal vein insulin assay. Apropos of a case]. / Localisation peropératoire de l'insulinome par dosage étagé de l'insuline portale. A propos d'un cas.

The diagnosis of insulinoma is easily done now but, in many cases, it is still difficult to locate it without the use of invasive procedures. With selective angiography and percutaneous transhepatic catheterization of the portal vein however, failure is reduced to about 4%. We report a case of a double localisation of insulinoma, revealed by an intraoperative catheterization of the splenic vein. The advantages of this method are discussed.

Utilization of oral sucrose load during exercise in humans. Effect of the alpha-glucosidase inhibitor acarbose.

We investigated the hormonal and metabolic response to a 100-g sucrose load given 15 min after adaptation to moderate-intensity (50% VmaxO2) long-duration (4-h) exercise in healthy volunteers. The effect of a 100-mg dose of the alpha-glucosidase inhibitor Acarbose ingested with the sucrose load was also investigated. "Naturally labeled [13C] sucrose" was used to follow the conversion to expired-air CO2 of the sugar ingested by isotope-ratio mass spectrometry. Circulating hormone and metabolite data were obtained in nine subjects, and indirect calorimetry and stable isotope methodology were applied to six of them. Under placebo, 93 +/- 4 g sucrose were entirely oxidized during the 4 h of exercise, total carbohydrate utilization was 235 +/- 14 g, endogenous carbohydrate utilization was 142 +/- 13 g, and total lipid oxidation was 121 +/- 7 g. A single oral dose of 100 mg Acarbose ingested with the sucrose load did not significantly modify total carbohydrate (239 +/- 2 g/4 h) or lipid (122 +/- 6 g/4 h) oxidation. In contrast, sucrose oxidation was reduced to 53 +/- 6 g/4 h and endogenous carbohydrate utilization increased to 186 +/- 7 g/4 h. Reduction of the rises in blood glucose and fructose and of the increases in plasma insulin and C peptide under Acarbose confirmed these effects, whereas lower circulating levels of alanine suggested a higher rate of gluconeogenesis. These data show that a 100-g glucose load ingested soon after initiation of exercise is a perfect available metabolic substrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic alterations after a two-hour nocturnal interruption of a continuous subcutaneous insulin infusion.

In order to evaluate the metabolic consequences of a 2-h nocturnal interruption of continuous subcutaneous insulin infusion (CSII), seven insulin-dependent diabetic patients without residual insulin secretion were investigated. The changes in blood glucose, plasma free insulin, glucagon, free fatty acids, and 3-hydroxybutyrate (3 OH-B) concentrations have been compared during two randomized tests carried out either during the normal functioning of a Mill-Hill pump from 10 p.m. to 8 a.m. (1.00 +/- 0.06 U insulin/h, keeping adequate metabolic control) or during the same conditions but with a deliberate arrest of the pump between 11 p.m. and 1 a.m. Considering the value recorded at 11 p.m. as reference, interruption of the insulin infusion resulted in: (1) a rapid (already significant after 1 h) and sustained (maximal fall: --12.5 +/- 2.5 mU/L at 3 a.m.) decrease in plasma free insulin; (2) a delayed (significant after 4 h) and linear rise in blood glucose (maximal increase: + 4.0 +/- 1.3 mmol/L at 5 a.m.); (3) an early (significant at midnight) and prolonged rise in plasma free fatty acids (+ 387 +/- 148 mumol/L at 3 a.m.); (4) a delayed (significant after 3 h) and sustained increase in plasma 3 OH-B (+ 347 +/- 88 mumol/L at 3 a.m.); and (5) no significant changes in plasma glucagon. Thus, a 2-h interruption of CSII in resting nocturnal conditions is sufficient to induce significant, delayed, and sustained metabolic alterations in C-peptide-negative patients despite good baseline blood glucose control. Resetting the pump at its basal rate is insufficient to quickly restore adequate circulating insulin levels and effectively counteract the metabolic disturbances. The efficacy of a bolus insulin injection in these conditions should be evaluated.

Effect of physical training on utilization of a glucose load given orally during exercise.

The effect of a 6-wk training period on the oxidation of a 100-g glucose load given orally during exercise was investigated in six healthy male volunteers. The subjects were submitted before and 24 h after the training program to a 105-min exercise bout (performed at about 40% of the pretraining VO2max) followed by a 90-min resting period. Naturally labeled [13C]glucose was given 15 min after the beginning of exercise. Exogenous glucose oxidation was derived from 13CO2 measurements in expired air, and total glucose and lipid oxidation were evaluated by indirect calorimetry. Training (60-min bicycling 5 days a week at 30-40% VO2max) resulted in a 29% increase in VO2max. During the 15 min of exercise that preceded glucose ingestion, the rate of total carbohydrate oxidation was slightly decreased after training, whereas the rate of lipid oxidation was slightly increased. Training did not affect the response of blood glucose, plasma insulin, or plasma free fatty acids to the glucose ingested during exercise; in contrast, the circulating levels of epinephrine, glycerol, and lactate were significantly reduced after training. Substrate utilization measurements revealed similar oxidation rates of carbohydrates (106.9 +/- 2.7 before vs. 100.2 +/- 4.7 g/3 h after training) and of lipids. However, detailed analysis revealed a significant 17% increase in exogenous glucose oxidation, thus indicating a significant sparing of endogenous carbohydrates. In conclusion, physical training induces a modest but significant increase in the oxidation of an oral load of glucose given during subsequent exercise of moderate intensity, a phenomenon reinforcing the sparing of endogenous carbohydrate stores.

Metabolic availability of glucose ingested 3 h before prolonged exercise in humans.

The aim of the present study was to investigate the extent to which an oral load of glucose ingested 3 h before a 4-h exercise bout of moderate intensity represents an energy source readily available during that exercise. Therefore, five healthy male volunteers drank 100 g of naturally labeled [13C]glucose dissolved in 400 ml of water, rested for 3 h, and then exercised on a treadmill for the next 4 h at about 45% of their individual maximum O2 consumption. Total glucose oxidation was derived from nonprotein respiratory quotient and exogenous glucose oxidation evaluated by the 13C methodology as previously described. Total carbohydrate oxidation averaged 285 +/- 17 g during the 7 h of the test, the global amount of carbohydrate oxidized during the exercising period was 253.1 +/- 16.9 g/4 h. Exogenous glucose oxidation averaged 11.3 +/- 0.7 g during the 3-h period of rest and increased markedly after the beginning of exercise, reaching 18.9 +/- 2.2 g/30 min during the first 30 min of exercise; the total amount of exogenous glucose oxidized during the 4 h of exercise was 67.5 +/- 9.4 g. Throughout the whole period of exercise, blood glucose concentrations remained between 3.5 and 4.0 mmol/l. Exercise induced a major fall in plasma insulin levels that reached undetectable values after 3 and 4 h, whereas plasma glucagon levels tended to rise, but their level never significantly exceeded the basal values; plasma free fatty acids and glycerol increased markedly during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Availability of glucose given orally during exercise.

Adequate utilization of glucose given orally during prolonged muscular exercise remains a matter of controversy. The aim of the present study was to investigate whether the time when glucose is ingested during exercise affects exogenous glucose disposal. Nine healthy male volunteers were submitted to a 4-h period of treadmill exercise at about 45% of their maximum O2 consumption. A 100-g load of naturally labeled [13C]glucose was given orally after 120 min (5 subj, group A) or 15 min (4 subj, group B) of exercise. In the 2 h after glucose ingestion, total carbohydrate oxidation (indirect calorimetry) was similar in both groups (A: 147 +/- 12 g/2 h; B: 135 +/- 12 g/2 h) as was lipid oxidation (A: 51 +/- 4 g/2 h; B: 57 +/- 11 g/2 h). Exogenous glucose oxidation was 54 +/- 2 g/h in group A vs. 55 +/- 6 g/2 h in group B. The blood glucose response to oral glucose was similar in the two conditions, whereas the C-peptide response, already modest, was further blunted when glucose was ingested after 2 h of exercise compared with the response observed after 15 min. In conclusion, glucose ingestion during prolonged exercise of moderate intensity is effectively oxidized, 55% of the load given being recovered as expired CO2 within 2 h; utilization of glucose given orally is similar when ingestion takes place 15 or 120 min after initiation of exercise.