B. Guerci

Maternally Inherited Diabetes and Deafness: A Multicenter Study

Mitochondrial (mt) gene abnormalities cause disease due to defects in oxidative production of energy (1). In 1990, Goto and colleagues (2) described the co-segregation of a syndrome called mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (which is sometimes associated with diabetes) and an A to G transition at position 3243 of mtDNA, encoding transfer RNA leucine (tRNALeu [UUR]). In 1992, a subtype of diabetes called maternally inherited diabetes and deafness (MIDD) was reported to co-segregate with the same point mutation (3, 4). Maternally inherited diabetes and deafness was initially characterized by matrilineal transmission, associated hearing loss, or both, without major neurologic defects. In MIDD, diabetes seems to be due primarily to a defect in insulin secretion (4-9), while insulin sensitivity is unaltered (8, 10). An estimated 0.5% to 2.8% of diabetic patients have MIDD (9, 11-16). Because most reported series have been small, the clinical description of MIDD and its course, particularly the occurrence of diabetic complications, remains incomplete. The aims of our study were to delineate the clinical presentation of MIDD, including involvement of other organs, in a large series of patients and to assess the prevalence of diabetic microvascular and macrovascular complications. Methods Patients We conducted this prospective multicenter descriptive study between September 1995 and December 1999. A questionnaire was sent to all members of the French Association for the Study of Diabetes (ALFEDIAM) in order to assess the clinical presentation of MIDD in a large series of patients. A total of 52 patients were included as a result of the questionnaire, and 19 patients were recruited directly from Lariboisire Hospital. The 3243 mtDNA mutation was identified in 40 probands who were selected primarily because they had both diabetes and deafness. Family screening identified 31 additional carriers of the mutation. All patients were white and European, except one who was of Caribbean origin. Three patients had mitochondrial encephalopathy, lactic acidosis, and strokelike episodes associated with diabetes. Among the 68 remaining patients, 54 had overt diabetes, 2 had impaired glucose tolerance, and 12 were healthy carriers. The study conformed to the principles of the Declaration of Helsinki, and all patients gave informed consent. Measurements We used a structured interview and a standardized examination of the patients and of their relatives to ascertain a family history of diabetes and hearing loss and to determine glucose tolerance disorders, treatment, diabetic complications, and associated manifestations. Abnormalities in glucose tolerance were diagnosed on the basis of the 1997 criteria outlined by the American Diabetes Association (17). Accordingly, diabetes was defined as a fasting plasma glucose level of 7 mmol/L (126 mg/dL) or greater on two occasions, a plasma glucose level of 11 mmol/L (200 mg/dL) or greater 2 hours after a 75-g oral glucose load, or both. In our study, we report only on the 54 patients with overt diabetes. Obesity was defined as a body mass index (BMI) of 30 kg/m2 or greater, body weight excess was defined as a BMI of 25 kg/m2 or greater, and low body weight was defined as a BMI less than 18.5 kg/m2 (18). Hemoglobin A1c level was assayed by using high-performance liquid chromatography. Islet-cell antibodies, antibodies to glutamic acid decarboxylase 65, or IA2 antibodies were determined in 32 cases. Hypertension was defined as a blood pressure exceeding 140/85 mm Hg on two occasions after 10 minutes in the resting position or as the use of antihypertensive treatment (19). Diagnosis of macrovascular complications (coronary heart disease, lower-limb arteriopathy, cerebrovascular disease) and diagnosis of cardiomyopathy were based on medical records, clinical examination, and appropriate tests (echocardiography, ultrasonography). We determined 24-hour urinary albumin excretion, proteinuria, and plasma creatinine concentration. A standardized ophthalmologic examination was performed in 49 patients, including ophthalmoscopy after pupillary dilation, color photographs, and fluorescein angiography, all of which were read by the same investigator. The retinal epithelium alterations were graded according to published criteria (20, 21). Molecular Studies The A to G 3243 mtDNA mutation was identified in peripheral blood leukocytes in 70 patients and from a buccal smear in 1 patient. Total DNA was extracted from the peripheral blood by using the conventional salting-out procedures. The 3243 mutation was detected by using 2% agarose electrophoresis after polymerase chain reaction amplification of a 294base pair fragment and enzymatic digestion with Apa I, as described elsewhere (2, 22). Statistical Analysis Data were stored and analyzed by using SPSS for Windows (SPSS Inc., Chicago, Illinois). Data are expressed as the mean (SD), with ranges indicated in parentheses. Differences in BMI and hemoglobin A1c levels among patient groups were assessed by using KruskalWallis analysis of variance. Correlations were analyzed by using the Spearman nonparametric rank correlation coefficient. Results Diabetes All 54 patients with overt diabetes (21 men, 33 women) had a fasting plasma glucose level greater than 7 mmol/L (126 mg/dL) when diabetes was diagnosed. Diabetes was diagnosed by systematic screening in 32 patients (59%). In the 22 remaining patients (41%), diabetes was revealed by the occurrence of polyuria, which was associated with ketoacidosis in 4 patients (7%). Age at diagnosis of diabetes was 38.8 9.6 years (range, 12 to 67 years); in 25 patients, diabetes was diagnosed before age 35. At the time of the study, the mean patient age was 50.0 10.3 years (range, 31 to 71 years), and diabetes duration was 11.8 8.7 years (range, 0 to 37 years). Diabetes was noninsulin-dependent in 22 patients (41%); 9 of 22 were treated with diet alone, and 13 were treated with sulfonylureas, metformin, or both. Twenty-five patients (46%) required insulin after experiencing secondary failure with a combination of maximally dosed sulfonylureas and metformin 9.9 5.8 years (range, 1 to 28 years) after diabetes was diagnosed. In 7 patients (13%), diabetes was insulin-dependent from its onset. Islet-cell antibodies were present in only 1 patient. A first-degree family history of diabetes was present in 33 of 40 probands (83%), and a maternal family history of diabetes was present in 29 probands (73%). No patient with MIDD was obese (Table), and 19 of 50 patients (38%) had low body weight. No correlation was found between BMI and hemoglobin A1c level, age, or diabetes duration. However, BMI and hemoglobin A1c values differed among patient groups according to treatment (Table). Table. Hemoglobin A1c Level and Body Mass Index in 54 Patients with Maternally Inherited Diabetes and Deafness Deafness Bilateral neurosensory hearing loss was present in 53 of 54 patients (98%). Hearing loss was clinically significant in all patients and was documented by audiography in 28 patients. Fourteen patients (26%) required a prosthetic hearing aid. Age at diagnosis of deafness was 34.6 13.9 years (range, 2 to 61 years). Twenty-five of 40 probands (63%) had a maternal history of deafness. Diabetes was the first clinical manifestation of the disease in 24 patients, and hearing loss was the first manifestation in 23 patients. In 7 patients, both conditions were diagnosed simultaneously. Macular Pattern Dystrophy We previously reported the presence of a characteristic macular pattern dystrophy in patients with MIDD (20). In our current study, macular pattern dystrophy was present in 42 of 49 examined patients (86%). Age at discovery was 46.5 10.8 years (range, 27 to 71 years). In 6 patients, the pigmented lesions were very small and were localized to the macula (grade 1) (Figure 1, top). In 27 patients, the deposits were more extensive and were localized around the macula and the optic disc (grade 2). In the 9 patients with advanced macular pattern dystrophy, the macula had patches of retinal atrophy (grade 3) (Figure 1, bottom). No correlation was found between grade of macular pattern dystrophy and age or diabetes duration. Figure 1. Macular pattern dystrophy. Top. Bottom. Visual acuity was normal in 43 of 49 patients (88%). Among patients with retinal atrophy, 4 had a visual acuity of 20/50 to 20/32 and 2 had a visual acuity below 20/63. Of the latter 2 patients, 1 had severe astigmatism and 1 had diabetic macular edema. Refraction was between +3 and 3 diopters in all patients with MIDD, except in 1 patient with severe astigmatism. No ocular nerve atrophy was observed. Neuromuscular Disorders Muscular disorders were observed in 22 of 51 documented cases of MIDD (43.1%). Patients reported painful muscle weakness that affected lower limbs during prolonged walking or running. In the 6 patients in whom it was performed, muscle biopsy showed ragged-red fibers typical of mitochondrial myopathy (Figure 2). Eight patients had cardiomyopathy; echocardiography showed typical left ventricular hypertrophy in all. Symptoms of congestive heart failure were present in 2 patients. A preexcitation syndrome (WolffParkinsonWhite) was present in 2 patients, and atrial fibrillation was seen in 1 patient. Mitochondrial myopathy was present in 4 of 8 patients with cardiomyopathy. Coronary heart disease was present in 4 of 54 patients (7%), and clinically significant peripheral artery lesions were observed in 2 of 54 patients. Hypertension was present in 15 of 53 patients (28%). Ocular motor palsy was present in 2 patients from the same family, and cerebellar ataxia with cerebellar atrophy on nuclear magnetic resonance imaging was seen in another patient. Atrophic changes in the brain were observed in the 4 other patients who underwent nuclear magnetic resonance imaging. Neuropsychiatric disturbances were present in 9 of 51 patients (18%). The

Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-5)

OBJECTIVE To compare the efficacy and safety of two doses of once-weekly dulaglutide, a glucagon-like peptide 1 receptor agonist, to sitagliptin in uncontrolled, metformin-treated patients with type 2 diabetes. The primary objective was to compare (for noninferiority and then superiority) dulaglutide 1.5 mg versus sitagliptin in change from baseline in glycosylated hemoglobin A1c (HbA1c) at 52 weeks. RESEARCH DESIGN AND METHODS This multicenter, adaptive, double-blind, parallel-arm study randomized patients (N = 1,098; mean baseline age 54 years; HbA1c 8.1% [65 mmol/mol]; weight 86.4 kg; diabetes duration 7 years) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, sitagliptin 100 mg, or placebo (placebo-controlled period up to 26 weeks). The treatment period lasted 104 weeks, with 52-week primary end point data presented. RESULTS The mean HbA1c changes to 52 weeks were (least squares mean ± SE): −1.10 ± 0.06% (−12.0 ± 0.7 mmol/mol), −0.87 ± 0.06% (9.5 ± 0.7 mmol/mol), and −0.39 ± 0.06% (4.3 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, dulaglutide 0.75 mg, and sitagliptin, respectively. Both dulaglutide doses were superior to sitagliptin (P < 0.001, both comparisons). No events of severe hypoglycemia were reported. Mean weight changes to 52 weeks were greater with dulaglutide 1.5 mg (−3.03 ± 0.22 kg) and dulaglutide 0.75 mg (−2.60 ± 0.23 kg) compared with sitagliptin (−1.53 ± 0.22 kg) (P < 0.001, both comparisons). The most common gastrointestinal treatment-emergent adverse events in dulaglutide 1.5- and 0.75-mg arms were nausea, diarrhea, and vomiting. CONCLUSIONS Both dulaglutide doses demonstrated superior glycemic control versus sitagliptin at 52 weeks with an acceptable tolerability and safety profile.

Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial.

OBJECTIVE To provide evidence-based options on how to intensify basal insulin, we explored head-to-head prandial interventions in overweight patients with type 2 diabetes inadequately controlled on basal insulin glargine with or without 1–3 oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS Patients were randomized to lixisenatide once daily or insulin glulisine given once or thrice daily, added to glargine, with or without metformin, if HbA1c remained ≥7 to ≤9% (≥53 to ≤75 mmol/mol) after 12 weeks of glargine optimization with OADs other than metformin stopped at the start of optimization. Coprimary end points at 26 weeks were 1) noninferiority (95% CI upper bound <0.4% [<4.4 mmol/mol]) in HbA1c reduction with lixisenatide versus glulisine once daily, and either 2a) noninferiority in HbA1c reduction for lixisenatide versus glulisine thrice daily or 2b) superiority in body weight change for lixisenatide versus glulisine thrice daily. Fasting and postprandial plasma glucose, composite efficacy/safety end points, and adverse events were also assessed. RESULTS Baseline characteristics were similar between arms (n = 298, diabetes and basal insulin duration of 12.2 and 3.2 years, respectively; BMI 32.2 kg/m2). HbA1c improved from 8.5% to 7.9% (69 to 63 mmol/mol) with glargine optimization and further to 7.2%, 7.2%, and 7.0% (55, 55, and 53 mmol/mol) with lixisenatide and glulisine once daily and thrice daily, respectively; all coprimary end points were met. Symptomatic hypoglycemia and body weight were lower in lixisenatide versus glulisine patients. More gastrointestinal events occurred with lixisenatide. CONCLUSIONS Short-acting glucagon-like peptide-1 receptor agonists as add-on to basal insulin may become a preferred treatment intensification option, attaining meaningful glycemic targets with fewer hypoglycemic events without weight gain versus basal-plus or basal-bolus in uncontrolled basal insulin-treated type 2 diabetes.

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.

Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience

OBJECTIVEnTo report a long-term multicentre experience with implantable insulin pumps in type 1 diabetic patients, and to test safety and accuracy of the systems following improvements in infused insulin solutions and peritoneal catheter.nnnRESEARCH DESIGN AND METHODSnForty MiniMed Implantable Pumps model 2001 were consecutively implanted over a two-month period in type 1 diabetic volunteers. The systems were equipped by a new compliant sideport catheter and were refilled at 45-day intervals with HOE 21 PH ETP insulin batches showing enhanced physical stability in vitro. Safety was assessed from the incidence of acute adverse events and effectiveness from quarterly HbA(1c) assays. Accuracy of delivery was measured at each pump refill by comparing residual insulin in the pump reservoir with expected amount according to programmed infusion. The study lasted until pump battery depletion or premature pump explantation.nnnRESULTSnCumulated experience was 106 patient-years. Premature explantations occurred in 3 cases, due to one electronic pump failure and two pump-pocket infections. Near-normal insulin delivery was sustained until expected battery depletion in 13 cases. Forty underdelivery events occurred in 24 pumps, but 36 among them were related to pump slowdowns due to insulin aggregation in pumps that were promptly solved by an outpatient NaOH rinse procedure. Only 4 underdeliveries were caused by catheter obstructions that required laparoscopy to remove peritoneal tissue overgrowth around the catheter. Over pump lifetime, HbA(1c) was 7.2 +/- 0.2% in the 13 patients with no underdelivery and 7.7 +/- 0.5% in the other ones. Only one severe hypoglycemia and one ketoacidosis occurred during the whole study.nnnCONCLUSIONnOur current experience with improved implantable pumps and insulin solutions shows both long-term safety and effectiveness of this treatment in type 1 diabetic patients following improvement in infused insulin solutions and catheter. This therapy may be a good alternative for patients that experience frequent severe hypoglycemia with intensive subcutaneous insulin therapy.

Heterogeneity of diabetes phenotype in patients with 3243 bp mutation of mitochondrial DNA (Maternally Inherited Diabetes and Deafness or MIDD)

OBJECTIVEnIn patients with maternally inherited diabetes and deafness (MIDD), due to 3 243 A > G mutation of mitochondrial DNA (mtDNA), diabetes may present with variable phenotypes.nnnOBJECTIVEnTo ascertain the existence of two distinct phenotypes, MIDD1 and MIDD2, in a series of patients with MIDD.nnnDESIGNnMulticenter prospective study.nnnPATIENTSn77 patients with diabetes and the mtDNA 3243 mutation and 139 control patients with type 1 (T1D) or type 2 (T2D) diabetes, matched according to initial presentation of diabetes, age at onset, sex, and duration of diabetes (24 T1D and 115 T2D, including 55 treated with insulin).nnnMEASUREMENTSnAnthropometric characteristics (height, body weight, body mass index [BMI], sex), family history of diabetes, and characteristics of diabetes (age at onset, treatment, hemoglobin A1c [HbA1c]), extrapancreatic manifestations.nnnRESULTSnIn 13 cases (17%, MIDD1), diabetes presented as insulin-dependent from the onset, with ketoacidosis in 6 cases. In 64 cases (83%, MIDD2), diabetes resembled T2D, and was treated with diet in 12 cases, oral hypoglycemic agents in 21 cases, or insulin in 31 cases. Compared with patients with MIDD2, patients with MIDD1 were characterized by lower age at onset of first manifestation of MIDD (25.4 +/- 9.6 vs 33.7 +/- 13.2 Years, P<0.0005), lower body weight (49.1 +/- 7.4 vs 56.3 +/- 10.9 kg, P<0.0025), lower BMI (18.2 +/- 2.3 vs 20.9 +/- 3.6 kg/m2, P<0.0005), and higher HbA1c levels (9.5 +/- 2.0 vs 7.5 +/- 1.6%, P<0.0005). Frequency of family history of diabetes and of extrapancreatic manifestations was the same in both MIDD subtypes. No difference was found within the MIDD2 subtype when comparing patients treated with or without insulin. Compared with matched controls, patients with MIDD had a lower BMI (MIDD1/T1D 18.2 +/- 2.3 vs 24.0 +/- 3.6 kg/m2 and MIDD2/T2D 20.9 +/- 3.6 vs 30.2 +/- 5.9 kg/m2, P<0.0025). Lastly, male patients with MIDD had a shorter height than controls (MIDD1/T1D: 166.1 +/- 3.2 vs 177.3 +/- 6.6 cm and MIDD2/T2D: 168.4 +/- 7.2 vs 173.6 +/- 6.6 cm P<0.025).nnnCONCLUSIONSnThese results confirm the existence of two different phenotypes in MIDD, MIDD1 and MIDD2, which may be related to the severity of the mitochondrial disease. The role of other genetic and/or environmental factors in the variable phenotype of MIDD remains to be elucidated.

Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a randomized, phase III study.

To compare the once‐weekly glucagon‐like peptide‐1 (GLP‐1) receptor dulaglutide with the dipeptidyl peptidase‐4 (DPP‐4) inhibitor sitagliptin after 104u2009weeks of treatment.

When to treat a diabetic patient using an external insulin pump. Expert consensus. Société francophone du diabète (ex ALFEDIAM) 2009

For years, external insulin pumps have enjoyed proven efficacy as an intensive diabetes treatment to improve glycaemic control and reduce hypoglycaemia. Since the last ALFEDIAM guidelines in 1995, however, basal-bolus treatment using a combination of long- and short-acting insulin analogues have emerged and could challenge, at a lower cost, the efficacy of pumps using rapid-acting insulin analogues, considered the gold standard of insulin treatment. Nevertheless, given its theoretical and practical advantages, some patients will derive more benefit from pump treatment. These cases have been carefully evaluated in the literature by a panel of experts appointed by ALFEDIAM to determine the indications for pump treatment. In patients with type 1 diabetes, persistent elevated HbA(1c) despite multiple daily injections (MDI), and repeated hypoglycaemia and high glycaemic variability, represent the most validated indications. In patients with type 2 diabetes, pump treatment may be indicated in cases of MDI failure to achieve HbA(1c) targets. Absolute contraindications are rare, and comprise severe psychiatric disorders, rapidly progressing ischaemic or proliferative retinopathy before laser treatment and exposure to high magnetic fields. Relative contraindications are mostly related to the patients lack of compliance or inability to cope with the treatment, and need to be evaluated individually to clearly assess the benefit/risk ratio for the given patient. However, as these conditions are progressive, there should also be annual reassessment of the appropriateness of pump treatment. Specific education on pump treatment initially and throughout the follow-up, delivered by experienced medical and paramedical teams, are the best guarantees of treatment efficacy and safety.

Access of children and adolescents with type 1 diabetes to insulin pump therapy has greatly increased in France since 2001

AIMnInsulin pump therapy is an emerging option in the management of type 1 diabetes (T1D), but it often remains unused. For this reason, in 2007, a French national survey was carried out to update the frequency of insulin pump use in the paediatric population compared with a previous survey done in 2001.nnnMETHODSnThe present survey was performed in hospital departments involved in paediatric diabetes management (n = 67) and in adult departments involved in adolescent diabetes management (n = 113). The number of T1D children (age < 18 years) treated in each department, with or without the use of an insulin pump, and the number of insulin pump therapies initiated during the previous year were collected.nnnRESULTSnA total of 60 paediatric and 28 adult centres responded, involving 9073 T1D children and adolescents (93% in paediatric departments). Of these patients, 1461 (16%) were treated by insulin pump, 89% of which were managed in paediatric centres. However, pump use was more frequent in adult than in paediatric centres (32% versus 18%, respectively). Also, 38% of insulin pumps were initiated during the year prior to the survey. In addition, in 2001, 140 children were treated with insulin pump in 13 paediatric centres (versus 56 centres in 2007).nnnCONCLUSIONnThe number of centres using insulin pump therapy for diabetic children and the number of children treated by insulin pump were increased fourfold and 10-fold, respectively, from 2001 to 2007, indicating greater access to pump therapy in the French paediatric population. The present survey is still ongoing to evaluate the decision-making criteria that influence the initiation of insulin pump therapy in T1D paediatric patients.

Real-time continuous glucose monitoring (CGM) integrated into the treatment of type 1 diabetes: Consensus of experts from SFD, EVADIAC and SFE

P.-Y. Benhamou, B. Catargi, B. Delenne, B. Guerci, H. Hanaire, N. Jeandidier, R. Leroy, L. Meyer, A. Penfornis, R.-P. Radermecker, E. Renard, S. Baillot-Rudoni, J.-P. Riveline, P. Schaepelynck, A. Sola-Gazagnes, V. Sulmont, N. Tubiana-Rufi, D. Durain, I. Mantovani Coordination: A. Sola-Gazagnes, J.-P. Riveline Societe Francophone du Diabete (SFD), Societe Francaise d’Endocrinologie (SFE) and EVADIAC group (EVAluation dans le Diabete des Implants ACtifs)