Anaemia and its risk factors and association with treatments in patients with diabetes: A cross-sectional study.

BACKGROUND: Anaemia is frequently seen in patients with diabetes and the main cause is renal failure. At all stages of renal failure, however, the prevalence of anaemia is higher in diabetes patients than expected for their glomerular filtration rate, suggesting that causes of anaemia other than renal failure are at work. The present cross-sectional study was conducted to investigate the possible iatrogenic causes of anaemia in patients with diabetes. SUBJECTS AND METHODS: This was a hospital-based cross-sectional study of all patients who had biological and clinical data covering a 2-year period. All had been in contact with the diabetes department either as outpatients or as inpatients mostly for educational purposes. Clinical factors, including type of diabetes, known diabetes complications, treatments received and biological data, were reviewed for their possible involvement in anaemia. RESULTS: A total of 4145 consecutive patients were included. Anaemia was observed in 1065 (25.7%) of them. Patients with anaemia were more frequently women and those with longer durations of diabetes. Haemoglobin concentrations were decreased, and prevalence of anaemia was increased at all stages of renal failure, already at stage 2, KDIGO classification. Anaemia patients were more frequently taking insulin, antiplatelet agents and renin-angiotensin system blockers (RASBs). After exclusion of patients with specific causes of anaemia, logistic regression analysis of all parameters correlated with anaemia on univariate analysis revealed that anaemia was associated with gender, antiplatelet agents and RASBs. CONCLUSION: This study has confirmed that anaemia is frequently seen in diabetes patients and strongly associated with renal failure (already at stage 2). Our observations highlight the adjuvant role of drugs, particularly RASBs, in the risk of anaemia in patients with diabetes.

Disagreement between capillary blood glucose and flash glucose monitoring sensor can lead to inadequate treatment adjustments during pregnancy.

OBJECTIVE: Continuous glucose monitoring tends to replace capillary blood glucose (CBG) self-monitoring. Our aim was to determine the agreement between CBG and a flash glucose monitoring system (Flash-GMS) in treatment decision-making during pregnancy. RESEARCH DESIGN AND METHODS: Insulin-treated women with either type 1 (n=25), type 2 (n=4) or gestational diabetes (n=4) were included. A Flash-GMS sensor was applied for 14 days. Women scanned the sensor whenever they monitored their CBG. The primary endpoint was the proportion of discordant therapeutic decisions they would have made based on Flash-GMS rather than CBG results. Glucose averages, mean absolute difference (MAD), mean absolute relative difference (MARD) and Flash-GMS accuracy were also estimated. RESULTS: Data for forty 14-day periods were available. Preprandial Flash-GMS and CBG values were 93±42mg/dL and 105±45mg/dL, respectively (P<10-4), and 2-h postprandial (PP) values were 106±45mg/dL and 119±47mg/dL, respectively (P<10-4). MAD was 14±22mg/dL preprandial and 15±24mg/dL 2-h PP; MARD was 19%; and 99% of glucose value pairs were within the clinically acceptable A and B zones of the Parkes error grid. Concordance rate for therapeutic decision-making was 80-85% according to ADA targets and 65-75% according to a pragmatic threshold. At different time points of the day, 83-92% of discordant results were due to Flash-GMS values being lower than their corresponding CBG values. CONCLUSION: Flash-GMS tends to give lower estimates than CBG. Thus, in cases requiring therapeutic changes to treat or prevent hypo- or hyperglycaemia, 25-35% of choices would have been divergent if based on Flash-GMS rather than CBG.

Early worsening of diabetic retinopathy after rapid improvement of blood glucose control in patients with diabetes.

AIM: To review the frequency, importance of and risk factors for "early worsening of diabetic retinopathy" (EWDR) after rapid improvement of blood glucose in patients with diabetes. METHODS: This was a systematic review of key references (PubMed 1980-2016) and the current international recommendations for the above-mentioned topics. RESULTS: EWDR has been described during intensive treatment (IT) in patients with uncontrolled type 1 or 2 diabetes, and after pancreas transplantation or bariatric surgery. EWDR arises in 10-20% of patients within 3-6 months after abrupt improvement of glucose control, and in nearly two times that proportion in patients with advanced baseline diabetic retinopathy (DR). While EWDR is often transient and predominantly driven by the development of cotton-wool spots and intraretinal microvascular abnormalities in patients with no or minimal DR, it can lead to irreversible retinal damage in patients with advanced DR before IT. Its identified risk factors include higher baseline levels and larger magnitudes of reduction of HbA1c, longer diabetes durations and previous severity of DR. CONCLUSION: Intensive diabetes treatment inducing a rapid fall in glucose should prompt vigilance and caution, particularly in patients with long-term and uncontrolled diabetes and DR prior to IT. Careful retinal examination should be performed in all patients before initiating IT; however, in patients with severe non-proliferative or proliferative DR, panretinal photocoagulation therapy should be performed promptly. During the year following IT, quarterly eye monitoring is required in patients at high risk of EWDR (long-term uncontrolled diabetes, previous advanced DR), whereas follow-up every 6 months can be applied in patients with short-term diabetes and no/minimal DR before IT. To date, there is no evidence that controlling the speed or magnitude of HbA1c decreases will reduce the risk of EWDR in patients with diabetes.

Anaemia, a common but often unrecognized risk in diabetic patients: a review.

Anaemia in patients with diabetes, both type 1 and type 2, is a frequent clinical finding. The mechanisms of anaemia are multifactorial and often not very well understood. Iatrogenic causes, including oral antidiabetic drugs, ACE inhibitors and ARBs, and renal insufficiency are the major causes of anaemia in patients with type 2 diabetes. In patients with type 1, the cause is often an associated autoimmune disease, and screening for autoimmune gastritis, pernicious anaemia, Hashimoto's thyroiditis, coeliac disease and Addison's disease is recommended. Other rare causes - including G6PD deficiency, microangiopathic haemolytic anaemia and thiamine-responsive megaloblastic anaemia - should be suspected in young patients or when the classical causes are excluded. Early detection and recognition of the cause(s) of anaemia in patients with diabetes could help to prevent other clinical manifestations as well as the complications of diabetes.

Effect of dietary protein on post-prandial glucose in patients with type 1 diabetes.

BACKGROUND: In flexible insulin therapy, determination of the prandial insulin dose only takes into account the carbohydrate content of the evening meal, and not the protein content. Protein can, however, contribute to gluconeogenesis. We compared the glycaemic effect of a standard evening meal with that of a test evening meal enriched in protein. METHODS: The present study was conducted in 28 C-peptide negative patients with type 1 diabetes. Two evening meals that were similar in content, except that one was enriched by the addition of 300 g of 0%-fat fromage frais, were taken on two consecutive days. Insulin doses were maintained exactly the same before both evening meals. Patients were monitored with a continuous glucose-monitoring device. RESULTS: Patients ate similar quantities at both evening meals, except for protein (21.5 g more at the test evening meal). The preprandial insulin dose was 0.96 (0.4) U per 10 g carbohydrates. After correction for differences of interstitial glucose at the start of the evening meals, both interstitial and capillary glucose levels were similar after both evening meals, except for the late-post-prandial interstitial glucose level. CONCLUSIONS: We found no effect of dietary protein on post-prandial-, overnight- or late-night glucose levels in patients with type 1 diabetes. This confirms that dietary proteins need not be included in the calculation of prandial insulin dose.

Zinc transporter (ZnT)8(186-194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients.

AIMS/HYPOTHESIS: Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets. METHODS: Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot. RESULTS: White HLA-A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153-161)). CONCLUSIONS/INTERPRETATION: ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity.

Pancreatic exocrine function in patients with diabetes.

BACKGROUND: Decreased function of the exocrine pancreas is frequent in patients with diabetes. Our aim was to investigate clinical correlates of pancreatic exocrine failure in patients with diabetes. PATIENTS AND METHODS: We investigated exocrine function by assaying both elastase-1 concentration and chymotrypsin activity in 667 patients. We conducted separate analysis on patients with Type 1 diabetes and patients with Type 2 diabetes. Patients were separated into three groups according to whether both elastase-1 concentration and chymotrypsin activity were normal, or one or both were altered. RESULTS: A total of 667 consecutive patients were analysed, including 195 with Type 1 and 472 with Type 2 diabetes. Elastase-1 concentration was <200 µg/g in 23% of the patients. Chymotrypsin activity was <6 U/g in 26% of the patients. In 66% of the patients elastase-1 concentration was >200 ug/g and chymotrypsin activity >6 U/g. One test was below threshold in 19%, both in 15%. In patients with Type 1 diabetes, the three groups defined by results of elastase-1 concentration and chymotrypsin activity differed with regard to duration of diabetes and prevalence of glutamic acid decarboxylase antibodies, but not BMI or HbA(1c) , or prevalence of retinopathy, neuropathy, nephropathy or vascular disease. In patients with Type 2 diabetes, the three groups differed with regard to BMI, use of insulin and vascular disease, but not known duration. CONCLUSION: Factors associated with pancreatic exocrine failure differ in patients with Type 1 diabetes compared with patients with type 2 diabetes. In patients with Type 2 diabetes, association of decreased pancreatic exocrine function with BMI and vascular disease suggests a role of pancreatic arteriopathy.

Ambulatory 24-hour fast using flexible insulin therapy in patients with type 1 diabetes.

AIM: Prolonged fasting may be necessary in life for religious, medical and other reasons. For this reason, our study investigated the feasibility and safety of a 24-h fast conducted at home for patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Thirty-four patients with type 1 diabetes performed a 24-h complete fast at home. Thirteen patients were treated with multiple insulin injections using either glargine (n=12) or NPH (n=1) as basal insulin. The remaining patients were treated with an insulin pump. All patients received their basal insulin only, which was adjusted to 40% of their total daily dose, and were monitored by either a Gold(®) or Guardian(®) continuous glucose monitoring (CGMS) device. Capillary glucose (SMBG) was targeted at 3.9-7.8 mmol/L, with a standardized protocol for correction of hyper- and hypoglycaemia. Interstitial glucose (IG) profiles were compared with the SMBG values; the IG profiles of patients using glargine or a pump and either of the two CGMS devices were also compared. RESULTS: All of the patients completed the 24-h fast with no major incident. At the end of the fast, 80% of the IG values were on target. The route by which insulin was delivered made no difference, but there were more IG values on target in patients monitored by the Guardian(®) device. IG was below target in 104 occurrences and above-target in 34. After a mean intake of 10 g of sucrose, below-target IG was corrected within 30 min [range: 15-40]. The mean insulin dose to correct above-target episodes was 1 U. CONCLUSION: Prolonged fasting is possible at home in patients with type 1 diabetes, provided the basal dose is adjusted. The use of CGMS is not necessary, but offers useful information on the patient's IG profile during the fast.

Poor prognosis of pregnancy in women with autoimmune type 1 diabetes mellitus masquerading as gestational diabetes.

AIM: To describe the clinical presentation and the prognosis of autoimmune type 1 diabetes (T1D) that was first revealed during pregnancy masquerading as gestational diabetes mellitus (GDM). METHODS: We reviewed the files of 21 women in whom diabetes was revealed during a pregnancy ("index pregnancy") and progressed to T1D after delivery, and in whom GAD and/or IA-2 autoantibodies were found. RESULTS: The median age and BMI of the women were 31 years and 19.8 kg/m(2). Eleven women had at least one risk factor for GDM. Eight of the 12 multiparous women had had an abnormal outcome of previous pregnancy, including GDM in five. GDM was diagnosed at week 26 (range: 4-38) of gestation by screening in 18, because of macrosomia in two and during hyperglycaemic crises in three. All were treated with insulin, from the time of diabetes diagnosis in 10 and after 4 weeks (range: 2-15) in 11. Term of delivery was 38 (range: 26-41) weeks. Abnormal outcomes occured in 14 pregnancies, including two fetal deaths, four preterm deliveries and eight macrosomic infants. No congenital malformations were reported. After delivery, insulin therapy was stopped in 18 women for 6 months (range: 2-48). The diagnosis of the autoimmune origin of diabetes was established during the index pregnancy in only eight cases. CONCLUSION: T1D may reveal as GDM in women with or without risk factors for GDM and is associated with a poor prognosis, partly because the correct diagnosis and treatment are delayed. Whether screening for autoimmune markers of T1D should be performed more systematically in women with GDM deserves to be studied.

Familial young-onset forms of diabetes related to HNF4A and rare HNF1A molecular aetiologies.

OBJECTIVE: We have dissected the rare molecular anomalies that may affect hepatocyte nuclear factor-1a (HNF1A) and hepatocyte nuclear factor-4a (HNF4A) in patients with familial young-onset diabetes for whom HNF1A mutations have been excluded by sequence analysis. METHODS: Eighty-four unrelatedHNF1A-negative patients with diabetes diagnosed before the age of 40 years, a family history of diabetes and the absence of features suggestive of Type 2 diabetes were included. We analysed by sequencing the HNF4A promoter and coding regions, the HNF1A promoter region and specific regions of HNF1A(B) and HNF1A(C) isoforms and searched for large deletions of HNF1A and HNF4A by multiplex ligation-dependent probe amplification (MLPA). RESULTS: We identified five novel HNF4A mutations (5 / 84, 6%), including four missense and one in-frame deletion, and one mutation of the HNF1A promoter (1 / 84). Sequence analysis of isoform-specific coding regions of HNF1A did not reveal any mutation. We next identified two whole gene deletions of HNF1A and HNF4A, respectively (2 / 84, 2.4%). CONCLUSIONS: Altogether, the search for rare molecular events in HNF1A and HNF4A led us to elucidate 8 / 84 (9.5%) of our HNF1A-negative cases.This study shows that genetic aetiologies remain to be elucidated in familial young-onset diabetes. It also highlights the difficulty of the differential diagnosis with Type 2 diabetes because of the wide clinical expression of monogenic young-onset diabetes and the absence of specific biomarkers.

Peak-time determination of post-meal glucose excursions in insulin-treated diabetic patients.

OBJECTIVE: This study aimed to determine the optimal time to measure peak blood glucose values to find the best approach for self-monitoring blood glucose after a meal. DESIGN AND METHODS: For this retrospective analysis, 69 ambulatory continuous glucose-monitoring system (CGMS) profiles were obtained from 75 consecutive insulin-treated patients with diabetes. The parameters measured were the peak post-meal blood glucose values, peak time, and rates of increase and decrease to and from the zenith of the resulting curves. RESULTS: The mean peak time after breakfast was 72+/-23 min, which was reached in less than 90 min in 80% of the patients. The apparent glucose rate of increase from pre-meal to the maximum postprandial value was 1.23+/-0.76 mg/dL/min, while the glucose rate of decrease was 0.82+/-0.70 mg/dL/min. Peak time correlated with the amplitude of postprandial excursions, but not with the peak glucose value. Also, peak times were similar after breakfast, lunch and dinner, and in type 1 and type 2 diabetic patients. CONCLUSION: To best assess peak postprandial glucose levels, the optimal time for blood glucose monitoring is about 1h and 15 min after the start of the meal, albeit with wide interpatient variability. Nevertheless, 80% of post-meal blood glucose peaks were observed at less than 90 min after the start of the meal.

The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.

CONTEXT: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. OBJECTIVE: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. PARTICIPANTS: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. RESULTS: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. CONCLUSIONS: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

Postprandial glycaemia: a plea for the frequent use of delta postprandial glycaemia in the treatment of diabetic patients.

Postprandial hyperglycaemia is a phenomenon often neglected by patients as well as doctors. While patients only voluntarily measure morning and preprandial capillary glycaemia, physicians do not encourage the measurement of anything further. The specific role of postprandial hyperglycaemia in the determination of late diabetes complications, such as micro- and macroangiopathy, remains controversial. It is however undeniable that the postprandial glycaemic excursion plays an important role in total hyperglycaemia reflected by an increase in glycated haemoglobin. The postprandial glycaemia measurement or, more appropriately, the postprandial glycaemic excursion (the difference between postprandial and preprandial glycaemia, also called the postprandial delta glycaemia), is important to measure and there are specific tools to correct it when abnormal. Postprandial delta glycaemia should lie between 30 and 50 mg/dl. It is thus suggested to measure it not necessarily on a daily basis, but when it is expected that the glycaemic couple, or "pre-postprandial couple", is high. The specific tools for treatment of postprandial hyperglycaemia can be dietetic (carbohydrate quantity reduction or ingestion of fiber-rich and/or low glycaemic index foods) or medicinal. Among the specific medicinal treatments are the alpha-glucosidase-inhibitors (which can be used for both type 1 and type 2 diabetic patients), glinides and fast-acting insulins. Rather than first treating fasting and interprandial hyperglycaemia, as has been commonly done by physicians, the authors recommend the simultaneous treatment of pre-, inter- and postprandial hyperglycaemia. The optimal time at which to evaluate postprandial glycaemia is approximately 1 h and 15 minutes for type 1 and type 2 diabetic patients.