Review of basal-plus insulin regimen options for simpler insulin intensification in people with Type 2 diabetes mellitus.

AIMS: To identify simple insulin regimens for people with Type 2 diabetes mellitus that can be accepted and implemented earlier in primary and specialist care, taking into consideration each individual's needs and capabilities. METHODS: Using randomized clinical trials identified by a search of the PubMed database, as well as systematic reviews, meta-analyses and proof-of-concept studies, this review addresses topics of interest related to the progressive intensification of a basal insulin regimen to a basal-plus regimen (one basal insulin injection plus stepwise addition of one to three preprandial short-acting insulin injections/day) vs a basal-bolus regimen (basal insulin plus three short-acting insulin injections per day) in people with Type 2 diabetes. The review explores approaches that can be used to define the meal for first prandial injection with basal-plus regimens, differences among insulin titration algorithms, and the importance of self-motivation and autonomy in achieving optimum glycaemic control. RESULTS: A basal-plus regimen can provide glycaemic control equivalent to that obtained with a full basal-bolus regimen, with fewer injections of prandial insulin. The first critical step is to optimize basal insulin dosing to reach a fasting glucose concentration of ~6.7 mmol/l; this allows ~40% of patients with baseline HbA1c >75 mmol/mol (9%) to be controlled with only one basal insulin injection per day. CONCLUSIONS: Compared with a basal-bolus regimen, a basal-plus insulin regimen is as effective but more practical, and has the best chance of acceptance and success in the real world.

Independent positive association of plasma ß-carotene concentrations with adiponectin among non-diabetic obese subjects.

PURPOSE: Many epidemiological studies find an inverse correlation between carotenoids intake or carotenoids plasma concentrations and body mass index (BMI), insulin resistance or metabolic syndrome in the general population. However, it is not clear whether these relationships occur in obese population. METHODS: We conducted a cross-sectional study in 108 obese non-diabetic patients. RESULTS: There was an inverse correlation between plasma levels of pro-vitamin A carotenoids (α-carotene, ß-carotene and ß-cryptoxanthin) and both BMI and insulin resistance (estimated by the HOMA-IR). No correlation between plasma concentrations of lycopene or lutein/zeaxanthin and BMI or insulin resistance was found. The inverse association between the three pro-vitamin A carotenoids and HOMA-IR disappeared after adjustment for BMI and waist circumference. Interestingly, we identified a positive association between concentrations of ß-carotene and adiponectin in plasma that was independent of sex, age, smoking status, BMI and waist circumference. To our knowledge, such association has never been described in obese patients. CONCLUSION: These results suggest the existence of a favourable effect of ß-carotene on insulin sensitivity in obese individuals that could involve a positive regulation of adiponectin, either directly or via its pro-vitamin A activity. The demonstration of the potential benefits of ß-carotene towards insulin sensitivity would open the way to dietary strategies to prevent metabolic syndrome.

Pharmacodynamics of the glucagon-like peptide-1 receptor agonist lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus poorly controlled on sulphonylureas with/without metformin.

AIMS: The PDY6797 study evaluated efficacy, safety and pharmacodynamics of lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus (T2DM) insufficiently controlled with sulphonylureas with/without metformin. METHODS: This randomized, double-blind, placebo-controlled trial comprised a single-dose assessment of lixisenatide 5 and 10 µg, and a 5- to 6-week repeated dose-escalation assessment of lixisenatide 5 to 30 µg once (QD) or twice daily (BID). The primary endpoint was change in postprandial plasma glucose (PPG) area under the curve (AUC)[0:29-4:30 h] after a standardized breakfast at the highest tolerated lixisenatide dose. Change from baseline in glycated haemoglobin (HbA1c), 2-h PPG and fasting plasma glucose (FPG) were assessed, as were adverse events. RESULTS: Change from baseline in PPG AUC[0:29-4:30 h] with lixisenatide QD and BID was significantly greater than placebo (p < 0.0001 for all study populations), with particularly prominent effects in Japanese patients. Greater reductions in PPG AUC[0:29-4:30 h] were seen with lixisenatide QD versus BID, while the totality of evidence suggested that the lixisenatide 20 µg dose was optimal. In the overall population, changes from baseline for 2-h PPG, HbA1c and FPG were significant with lixisenatide QD and BID versus placebo (p < 0.01 for all). Lixisenatide was well tolerated. CONCLUSIONS: Lixisenatide significantly reduced PPG AUC[0:29-4:30 h] versus placebo at the highest well-tolerated dose in patients with T2DM treated with sulphonylureas with/without metformin and had a good safety and tolerability profile. Japanese patients experienced particular benefits with lixisenatide in terms of reductions in PPG excursions.

Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii.

BACKGROUND: Obesity is associated with increased health risk and has been associated with alterations in bacterial gut microbiota, with mainly a reduction in Bacteroidetes, but few data exist at the genus and species level. It has been reported that the Lactobacillus and Bifidobacterium genus representatives may have a critical role in weight regulation as an anti-obesity effect in experimental models and humans, or as a growth-promoter effect in agriculture depending on the strains. OBJECTIVES AND METHODS: To confirm reported gut alterations and test whether Lactobacillus or Bifidobacterium species found in the human gut are associated with obesity or lean status, we analyzed the stools of 68 obese and 47 controls targeting Firmicutes, Bacteroidetes, Methanobrevibacter smithii, Lactococcus lactis, Bifidobacterium animalis and seven species of Lactobacillus by quantitative PCR (qPCR) and culture on a Lactobacillus-selective medium. FINDINGS: In qPCR, B. animalis (odds ratio (OR)=0.63; 95% confidence interval (CI) 0.39-1.01; P=0.056) and M. smithii (OR=0.76; 95% CI 0.59-0.97; P=0.03) were associated with normal weight whereas Lactobacillus reuteri (OR=1.79; 95% CI 1.03-3.10; P=0.04) was associated with obesity. CONCLUSION: The gut microbiota associated with human obesity is depleted in M. smithii. Some Bifidobacterium or Lactobacillus species were associated with normal weight (B. animalis) while others (L. reuteri) were associated with obesity. Therefore, gut microbiota composition at the species level is related to body weight and obesity, which might be of relevance for further studies and the management of obesity. These results must be considered cautiously because it is the first study to date that links specific species of Lactobacillus with obesity in humans.

Treating type 2 diabetes: how safe are current therapeutic agents?

Sulphonylureas (SUs) and biguanides (metformin) are the current mainstays in the treatment of type 2 diabetes (T2DM) and represent the most commonly used oral hypoglycaemic agents (OHAs). In recent years, a variety of new OHAs have become available, including thiazolidinediones, glinides, alpha-glucosidase inhibitors, glucagon-like peptide-1 agonists, amylin analogues and dipeptidyl peptidase-IV inhibitors, providing physicians with a larger therapeutic catalogue than ever before. The traditional drugs metformin and SUs have an established safety profile through long-term use. However, long-term clinical trials and routine use are lacking for many of the new agents, and some potentially serious side effects have been reported with several of these compounds. Until adequate data is obtained, it is difficult to assess the risk-benefit ratio of these agents in relation to the traditional drugs. Until that becomes fully documented, it may be wise to start pharmacologic treatment of patients on an individual basis, weighing the benefits and costs of each medication. Thus, there remains a place for well-established drugs that have a proven safety record and are supported by years of clinical use for the treatment of T2DM.

Options for the intensification of insulin therapy when basal insulin is not enough in type 2 diabetes mellitus.

In the early treatment of type 2 diabetes mellitus (T2DM), the addition of a basal insulin, such as insulin glargine, to existing oral therapy can help patients attain recommended glycaemic control targets, including haemoglobin A(1c) (HbA(1c)) <7% and fasting blood glucose <5.5 mmol/l (<100 mg/dl). For patients close to but not at target, the management of postprandial glucose excursions with a rapid-acting insulin, such as insulin glulisine, can provide further improvements in glycaemic control. In this review, the options for intensifying insulin therapy with the addition of one or more daily doses of prandial insulin are discussed. In addition, the advantages/disadvantages of choosing a basal-bolus vs. a premixed insulin strategy are discussed. A conceptually simple approach for the treatment of T2DM is for optimization of the basal insulin dose (added to oral antidiabetic drugs) to target fasting glycaemia followed by the addition of a single prandial dose of rapid-acting insulin to target the largest glucose excursion. A second and third dose of prandial insulin can then be added if HbA(1c) remains above target and to manage postprandial glucose excursions at other meals. Prospective studies are underway to further examine this concept and determine the benefit of this approach not only on overall glycaemic control but also on cardiovascular risk.

Therapeutic approach of type 2 diabetes mellitus with GLP-1 based therapies.

The goal of this review is to think about how to incorporate the GLP-1 based agents, represented by the dipeptidyl peptidase-4 (DPP-4) inhibitors or the glucagon-like peptide-1 (GLP-1) analogs, in the guidelines for the management of type 2 diabetes (T2DM). Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA(1c) (absolute values) by 0.5-1.1% (5 to 12%, relative values), with few adverse events and no weight gain. The sub-cutaneous injected GLP-1 analogs show larger reductions in HbA(1c) (0.8-1.7%, absolute values; 9.4-20.0%, relative values), associated with weight loss (1.75-3.8 kg); their most common adverse events are gastrointestinal symptoms which contribute to a substantial treatment interruption. If they do not challenge the use of metformin as the initial therapy of T2DM, several studies argue in favour of the use of DPP-4 inhibitors, either in combination with metformin as the initial treatment or, in add-on therapy to metformin. The advantages of this combination over others currently used are reviewed. In patients not tolerating metformin, DPP-4 inhibitors seem to be an excellent alternative as a monotherapy. As long as oral triple therapy is concerned, the choice for the association metformin + thiazolidinedione + incretin-based drug, has again several theoretical advantages against other triple therapy combinations. Finally, in patients with T2DM inadequately controlled with maximal tolerated oral multi-therapies, GLP-1 agonists are a good alternative to insulin therapy, allowing reaching a better glycaemic control together with a weight loss. However, for patients who do not tolerate GLP-1 agonist treatment, and for those not reaching the HbA(1c) target, insulin will remain necessary, allowing getting a better metabolic control, with few adverse events. The long-term effect of these new agents on glycaemic control has not yet been established, and their potential impact on beta-cell function in humans remains an area of active investigation. So, further studies are needed and will allow progressively refining the use of incretin-based agents in T2DM treatment strategy.

Treatment of diabetes mellitus using an external insulin pump: the state of the art.

The aim of diabetes treatment is to achieve tight glucose control to avoid the development of chronic diabetic complications while reducing the frequency of hypoglycaemic episodes. Continuous subcutaneous insulin infusion (CSII) using an external pump is an intensive diabetes therapy recognized to improve metabolic control and glycaemic instability, and to reduce the frequency of severe hypoglycaemia. For years, the theoretical advantages of the insulin pump (constancy of basal delivery, adjustable basal rates, and low insulin depots allowing the reduction of glycaemic variability) have contributed to its reported superiority compared with multiple daily injections (MDI). However, insulin pump therapy is now challenged by new MDI regimens based on long-acting insulin analogues that could replace the use of CSII. As a consequence, health professionals now have to determine which patients are likely to benefit the most from CSII. Recently, several studies reported that children and adolescents, and patients whose blood glucose imbalance was initially the most pronounced with basal-bolus regimens, would particularly benefit from CSII. Other indications were also proposed in marginal clinical situations with highly selected patients in whom a significant improvement of blood glucose was demonstrated. Finally, the use of CSII in type 2 diabetic patients now appears to be a good alternative to the ineffective MDI regimens observed in some of these patients. However, past experience with CSII indicates that candidates for insulin pump therapy must be carefully selected and strongly motivated to improve their glucose control. Use of CSII also requires strict medical supervision by physicians and a regular programme of patient education by paramedical teams, to ensure optimal responsible use of this technique by healthcare professionals.

Aggressive multimodal therapy of sporadic malignant insulinoma can improve survival: a retrospective 35-year study of 12 patients.

AIM: Sporadic malignant insulinoma (SMI) is a rare disease, and the consequent paucity of data in the literature and the development of aggressive treatments for liver metastases have led us to retrospectively analyze a series of 12 cases of SMI. METHODS: Every patient presenting with SMI, according to the WHO 2004 histopathology criteria, between 1970 and June 2005 in Marseille was included in the study. Patients with multiple endocrine neoplasia type 1 (MEN-1) and tumours of uncertain malignant potential were excluded. RESULTS: The ratio of male/female was 4/8, and mean age at diagnosis was 52.5 years. A 48-h fasting test in 10 patients was conclusive in nine, after a mean duration of 12 h 45 min. SMI size ranged from 7-120 mm (mean 30.3mm). Six patients had liver metastases and one had isolated lymph-node invasion. Surgery was performed in 12 patients. Five persisting diseases (mean follow-up of 1.8 years) required other treatments (chemoembolization, radiofrequency thermoablation [RFTA], liver transplantation); one patient relapsed 8.5 years after surgery; six were still in complete remission (mean follow-up of 5.8 years), and one patient had died by the time of the 24-month follow-up. CONCLUSION: Aggressive sequential multimodal therapy can prolong the survival of patients with SMI even in the presence of liver metastases.

Basal insulin treatment intensification in patients with type 2 diabetes mellitus: A comprehensive systematic review of current options.

AIM: As type 2 diabetes mellitus progresses, most patients require treatment with basal insulin in combination with another agent to achieve recommended glycaemic targets. The purpose of this systematic review was to examine the evidence supporting the use of the available add-on treatments [rapid-acting insulin (RAI), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors] to basal insulin. METHODS: MEDLINE, EMBASE and EBSCOhost were searched for English-language articles, and all those captured were original articles (case studies and narrative reviews were omitted). Data on study design, population demographics, interventions and outcomes were tabulated. The extracted outcome data included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), as well as body weight and safety data. RESULTS: A total of 88 publications were deemed relevant. All treatments reduced HbA1c and FPG. The most pronounced reductions in PPG, an unmet need in patients not controlled by basal insulin, were seen following administration of RAIs and short-acting GLP-1 RAs, although data for this outcome are generally lacking. Body weight benefits were observed with GLP-1 RAs and SGLT-2 inhibitors. However, as only articles in English were included, the result was a possible publication bias, while the diversity of study designs and drug combinations limited comparisons between studies. CONCLUSION: The evidence supports effectiveness of the available add-on treatments to basal insulin. However, other factors, such as potential body-weight increases, convenience/compliance and adverse events, particularly hypoglycaemia, should be considered on a patient-by-patient basis to optimalize treatment outcomes.

Importance of blood glucose management in the multifactorial approach of absolute cardiovascular risk in type 2 diabetes: the lessons from the Steno 2 study.

The problem of blood glucose as a cardiovascular risk factor has long been debated. Indeed, increasing arguments confirm the importance of blood glucose on cardiovascular risk, as shown by the results from epidemiological studies and therapeutic investigations. However, the literature has demonstrated the importance of postprandial blood glucose, or post-load-glucose, on cardiovascular risk. One could think that blood glucose, in particular postprandial blood glucose, is an independent, although not major, cardiovascular risk factor compared to other classical risk factors such as hypercholesterolemia, high blood pressure, and smoking, but it potentiates the risk when it coexists with these classical risk factors. This explains the increased prevalence of cardiovascular morbi-mortality in diabetic patients, in particular type 2 diabetes. Multifactorial treatment can reduce the cardiovascular risk by 55%, as the Steno 2 study demonstrated.

Alternatives routes of insulin delivery.

Optimal glycaemic control is necessary to prevent diabetes-related complications. An intensive treatment, which could mimic physiological insulin secretion, would be the best one. However subcutaneous insulin treatment is not physiologic and represents a heavy burden for patients with type 1 and type 2 diabetes mellitus. Consequently, more acceptable, at least as effective, alternative routes of insulin delivery have been developed over the past years. Up to now, only pulmonary administration of insulin (inhaled insulin) has become a feasible alternative to cover mealtime insulin requirements and one of the various administration systems was recently approved for clinical use in Europe and the United States. But, due to advances in technology, other routes, such as transdermal or oral (buccal and intestinal) insulin administration, could become feasible in a near future, and they could be combined together to offer non-invasive, efficacious and more physiological way of insulin administration to patients with diabetes.

C-peptide replacement improves weight gain and renal function in diabetic rats.

AIM: Recent experimental and clinical data suggest that C-peptide replacement during type 1 diabetes exerts beneficial effects on diabetic nephropathy. The aim of this study was to determine if physiological C-peptide administration in replacement dose during 28 days had beneficial effects on metabolic status and renal functions in type-1 diabetic rats. METHODS: Four groups of rats were investigated: a non diabetic group treated with buffer (C group, n=6), three streptozotocin diabetic-induced groups treated with either buffer (D group, n=6), insulin (D-I group, n=6) or rat homologous C-peptide (D-C group, n=6). Weight gain was measured every week. All animals were housed in metabolic cages on day 28 for assessment of metabolic data. Blood and urine samples were collected to allow measurement of plasmatic osmolality, C-peptide concentration, sodium, and glucose losses and proteinuria. Glomerular filtration rate (GFR) was determined by creatinine clearance. RESULTS: All streptozotocin-treated animals were diabetic. Glycaemic control (mg/dl), was markedly improved in D-I (133+/-65) when compared with either D (547+/-49, P<0.05) or D-C (520+/-48, P<0.05) groups. Conversely, weight gain during the study, was improved in D-I and D-C as compared with D animals (135+/-13 and 41+/-18 vs 18+/-21 respectively), despite different glycaemic control. Diabetes-induced glomerular hyperfiltration (ml/min/kg), urinary protein leakage (g/kg/day), and Na urinary losses (mmol/100 g/day) respectively, were significantly (P<0.05) reduced in D-C (3.95+/-0.6; 0.08+/-0.06; 1.5+/-0.9) in comparison with D (4.95+/-0.8; 0.18+/-0.16; 3.7+/-2.1) and D-I (5+/-0.9; 0.19+/-0.11; 2.7+/-0.8) animals. Plasmatic osmolality was significantly increased in D group whereas there were no differences between C group and D-C group. Food and water intakes, urinary volume as well as urinary glucose losses were not significantly different between D-C and D groups. CONCLUSIONS: C-peptide administration in replacement dose to streptozotocin diabetic rats induces weight gain regardless hyperglycaemia or glycosuria. Diabetic animals supplemented with C-peptide exhibit better renal function resulting in reduced urinary sodium waste and protein excretion together with reduction of the diabetes-induced glomerular hyperfiltration.

Insulin initiation in type 2 diabetic patients admitted in hospital in France and follow-up at 1 year.

OBJECTIVES AND METHODS: The IDAHO 2 epidemiological survey was conducted in departments of diabetology in insulin-naïve type 2 diabetics for whom insulin was initiated. The objective was to assess the patients' profile, the treatments proposed during hospital stay and after one year. RESULTS: 797 patients were analysed. Their characteristics were: age 64+/-12 years, 49% males, weight: 78+/-17 kg, BMI: 29+/-6 kg/m2, diabetes duration 11 years, prevalence of complications: 68%, fasting blood glucose 13+/-6 mmol/l, HbA1c: 10+/-2.2%; treatment prior to insulin comprised: at least 2 OHA: 71% of cases, one: 21%, no OAD: 8%. At hospital discharge, 54% of the patients used basal insulin. After 1 year, 670 continued on insulin. The insulin initiation was accompanied by a decrease in the FBG level (baseline: 13+/-6 mmol/l; final: 8.5+/-2.75 mmol/l; P<0.0001) and a HbA1c improvement (baseline: 10+/-2.2%; final: 7.9+/-1.4%; P<0.0001). This was observed du-ring the first 6 months (HbA1c: 7.8%, P<0.0001 versus baseline). 80% of the patients remained on the same insulin regimen after 1 year: 35% had 1 injection/day, 44% had 2, 12% had 3 and 9% had a complex regimen. The weight gain, the final daily dose and hypoglycaemias increased with the number of injections. The mean daily insulin dose was 33 U/day (24 U with 1 injection/day). CONCLUSION: The IDAHO study shows that insulin is effective in type 2 diabetics however, management is inadequate with insulin therapy being initiated too late and at doses which are low after one year.

[Management of diabetes in elderly cardiac patients]. / Prise en charge du diabète chez le coronarien âgé.

In 1998, data from the Assurance Maladie (national health insurance) showed that 11.2% of people over 65 years old, and thus corresponding to the World Health Organisation's definition of being elderly, were diabetic. More recently the Entred trial, a national sample representative of diabetics, clarified the characteristics, the state of health and the medical management of diabetes in patients aged over 65 years. Among the randomly selected 10,000 adults in this study, 5350 subjects (54% of the Entred population) were over 65 years old. Other studies indicate that more than a million subjects aged over 65 years are diabetic and that 25% of diabetics are aged over 75 years. The growing proportion of elderly people in the French population, plus the improvement in the detection and the better management of diabetes are bound to contribute to a further increase in the prevalence of diabetes in elderly subjects.

Determination of portal insulin absorption from peritoneum via novel nonisotopic method.

The absorption mechanism of insulin administered in the peritoneal cavity (IP) is of current interest because of the near availability of implantable insulin-infusion devices for the treatment of diabetes. To determine the fraction of insulin absorbed by the portal circulation after IP administration, a novel nonisotopic method is described. Conscious fasting diabetic dogs were studied at normoglycemia via the euglycemic insulin-clamp method. Posthepatic appearance of insulin and C-peptide were measured in peripheral blood during IP or intravenous (IV) equimolar infusion of insulin and C-peptide at two sequential 3-h infusion rates of 3.2 and 12.8 pmol.kg-1.min-1. Prior studies have shown that 40-60% of portal insulin is extracted at first pass by the liver, whereas C-peptide is not extracted. Thus, the fraction (F) of IP insulin not taken up by liver at first pass and consequently the fraction absorbed by the portal circulation can be derived from insulin (I) and C-peptide (C) plasma concentration values at steady state with a monocompartmental model where F = (IIP/IIV)(CIV/CIP). The mean +/- SE value of F was 49.7 +/- 8.8%. Glucose disappearance rates were lower with IP than IV infusion but similar when peripheral insulin levels were matched. We conclude that IP insulin is almost entirely absorbed by the portal circulation and induces lower glucose disappearance rates than IV insulin because of lower peripheral circulating insulin levels. Whether these properties make the IP route a more appropriate route for insulin therapy than the subcutaneous or IV routes remains to be established.

Metabolic factors and the foveal avascular zone of the retina in diabetes mellitus.

AIM: To study the foveal avascular zone (FAZ) of the central retina in diabetic patients with retinopathy having undergone metabolic evaluation. METHODS: One hundred and ten digital fluorescein angiograms were chosen from our digital image bank after cross matching diabetic patient lists of the ophthalmology and endocrinology departments of our institution. The patients had undergone day visits with systemic, biological and ophthalmologic evaluation, including digital fluorescein angiography. RESULTS: Sex ratio was M 62/F 48. Average age was 52.4 years (+/- 13.8) with 44 type 1 diabetics and 66 type 2. Retinopathy was present in all patients (54 background (BDR), 30 pre-proliferative (PPDR), 26 proliferative (PDR)). Age was positively correlated with FAZ grade (47.3 years +/- 13.2 for normal FAZ, 53.8 years +/- 13.7 for abnormal FAZ, P=0.03). Lipid profile showed a protective tendency of the Apo A1 fraction of cholesterol on macular vascularization (1.7 gr./l in normal FAZ patients vs 1.43 gr./l in abnormal FAZ patients, P=0.004). Body mass index was negatively correlated with macular ischemia (28.11 if FAZ not severely altered, 25.97 if FAZ severely altered, P=0.03). CONCLUSIONS: We found possible relations between BMI and Apo A 1 cholesterol and macular vascularization which may warrant further investigation.

Epidemiology and costs of diabetes treated with insulin in France.

Extrapolating from the results of the 1998 and 2000 French National Sickness Insurance Fund surveys, it can be estimated that at the end of 2002, 3.4% of the French population, i.e. 2,150,000 individuals, had diagnosed type 1 or type 2 diabetes mellitus. Among these individuals, 2,050,000 were taking drug treatments and about 100,000 were treated with diet alone. About 16.3% of diabetics given drug treatments were taking insulin, alone or in combination with oral antidiabetic drugs, i.e. approximately 447,000 individuals including 316,000 (70.6%) with type 2 diabetes. Regarding all individuals with type 2 diabetes, the percentage treated with insulin (alone or in combination with oral antidiabetic drugs) increased from 12.3% in 1998 to 16.5% in 2002, for a mean increase of 7.4% per year. This rate is globally corroborated, although the study periods are not exactly comparable, by changes in sales volumes for insulin observed over recent years showing an even more rapid mean annual growth of 13.4%. The difference between these two estimates suggests that either the mean dose of insulin delivered is increasing or that the increase in the number of treated diabetics is underestimated by the National Sickness Insurance Fund. Mean age of patients treated with insulin alone (type 1 and type 2 diabetics considered together) was 56.3 years with a median of 60 years and a sex ratio (M/F) close to 1 (0.9). There are no national data detailing monitoring practices in insulin-treated patients. Published analyses focus on type 2 diabetics treated with oral antidiabetic drugs and often exclude patients taking insulin. Blood glucose control is poor (HbA1c>8%) in approximately one-third of patients with type 2 diabetes and different studies have shown that in France among subjects with type 2 diabetes 3.1% are taking two oral antidiabetic drugs or more at maximal doses and have poorly controlled blood glucose levels. The percentage of insulin-treated diabetics is increasing steadily, but remains lower than observed in other European countries (generally reported in the 24% to 30% range). This special situation in France could fade out in upcoming years with better awareness of the importance of metabolic control, improved insulin therapy in this context, and improved conditions for use of insulin.

Erythrocyte Na(+)-K(+)-ATPase activity, metabolic control, and neuropathy in IDDM patients.

OBJECTIVE: To study the relationship among red blood cell Na(+)-K(+)-ATPase activity, metabolic control, and diabetic neuropathy. RESEARCH DESIGN AND METHODS: Na(+)-K(+)-ATPase activity has been measured in the red cell membrane of 43 long-standing IDDM patients (duration of diabetes 17.5 +/- 2 years, mean +/- SE), with 20 of the patients presenting with peripheral neuropathy. There were 23 healthy subjects serving as the control group. RESULTS: Na(+)-K(+)-ATPase activity was significantly lower in diabetic patients than in healthy subjects (236.5 +/- 7.5 vs. 294 +/- 10 nmol P1 . mg protein-1 . h-1, P < 0.05). Among diabetic patients, Na+/K(+)-ATPase activity was not dependent on the degree of diabetic control, nor was it correlated with either fasting blood glucose (r = 0.16, NS) or HbA1 (r = 0.01, NS). Na(+)-K(+)-ATPase activity was lower in patients with neuropathy than in those without it (212 +/- 8.5 vs. 261 +/- 6.6, P < 0.05). Furthermore, in a subgroup of 20 patients, a positive correlation was observed between erythrocyte Na(+)-K(+)-ATPase activity and nerve conduction velocity in the peroneal (r = 0.558, P < 0.02) and tibial nerve (r = 0.528, P < 0.05). CONCLUSIONS: These results suggest that diabetes-induced Na(+)-K(+)-ATPase activity dysfunction could be implicated in the pathogenesis of human diabetic neuropathy and the electrophysiological abnormalities observed in these patients.

Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients.

OBJECTIVE: To compare intraperitoneal implantable insulin infusion (IP) to subcutaneous (SC) intensive insulin therapy. RESEARCH DESIGN AND METHODS: Twenty-one insulin-dependent (type I) diabetic patients aged 24-61 yr underwent a 3-mo treatment optimization using multiple SC daily injections or external pumps. Patients were then randomized (time 0 mo) to IP infusion using Infusaid-programmable pumps or continuation on SC intensive insulin for 6 mo. RESULTS: No differences were noted between study and control group data. However, longitudinal within-group comparisons from baseline showed that glycosylated hemoglobin improved to near-normal in both groups: IP, 9.0 +/- 0.5 vs. 7.8 +/- 0.6% (P less than 0.05) and SC, 8.4 +/- 0.5 vs. 7.5 +/- 0.3% (P less than 0.5) at 0 and 4 mo, respectively (normal less than 6.9%). The percentage of blood glucose tests greater than 11 mM at 0 and 6 mo was 28 +/- 5 vs. 16 +/- 4% in the IP group (P less than 0.05) and 22 +/- 5 vs. 24 +/- 7% in the SC group (NS). At 0 and 6 mo, the standard deviation of blood glucose values, an index of glycemic fluctuations, was 4.3 +/- 0.4 vs. 3.2 +/- 0.5 mM in the IP group (P less than 0.05) and 3.7 +/- 0.3 vs. 4.0 +/- 0.4 mM in the SC group (NS). Weight, insulin dosages, circulating lipid levels, and the frequency of severe hypoglycemic reactions and biochemical hypoglycemias were similar and did not change in the two groups. CONCLUSIONS: IP-implantable pumps compared with SC intensive insulin therapy have similar effects on most metabolic variables and are equally effective at achieving near-normal glycemic levels. Only longitudinal data suggest that IP treatment may be more effective at limiting glycemic fluctuations.