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.

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.

Pancreatic islet beta cells drive T cell-immune responses in the nonobese diabetic mouse model.

The role of autoantigens and that of target organs in which tissue lesions develop remains elusive in most spontaneous models of autoimmune diseases. Whether the presence of target autoantigens is required for the recruitment of autoreactive lymphocytes is unknown in most cases. To evaluate the importance of islet cells in the development of autoimmunity in the nonobese diabetic (NOD) mouse, we generated beta cell-deprived mice by injecting a high dose of alloxan, a toxic agent specific for beta cells. In contrast with spleen cells from 6-mo-old naive NOD mice which transfer diabetes in irradiated 8-mo-old male recipients, spleen cells from age-matched NOD mice which received a single injection of alloxan at 3 wk of age did not transfer diabetes. With the exception of the ability to transfer diabetes, beta cell-deprived NOD mice showed maintained immune competence. Furthermore, sialitis developed with the expected intensity and prevalence in beta cell-deprived mice. Already committed "diabetogenic" spleen cells collected from spontaneously diabetic mice also showed a reduced capacity to transfer diabetes after their removal from the diabetic mice and transient "parking" in beta cell-deprived mice. Taken together, our data bring evidence that involvement of autoreactive T cells detected by the capacity to transfer diabetes requires the presence of target beta cells.

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.

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.

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.

Weight gain and insulin treatment.

This review presents recent data on weight gain when on insulin treatment in type 1 and type 2 diabetic patients. In both types of diabetes, the excess weight gain with intensified insulin therapy compared with conventional insulin or sulfonylurea remains modest: 2.6 kg over 7.5 years in the Stockholm study (type 1 diabetic patients) and 1.7 kg when compared to glibenclamide over 10 years in the UKPDS (type 2 diabetic patients). Patients who gain the most weight after insulin initiation are those who: (1) had the worst metabolic control before the intensification of treatment, (2) had the greater weight loss prior to insulin initiation, and (3) in the case of patients with type 1 diabetes, have a family history of type 2 diabetes. This suggests that most of the weight gain observed after the insulin initiation is a "catch-up" weight re-gain. There is no evidence that weight gain after insulin therapy initiation is associated with a deterioration in the lipid profile or arterial hypertension or an excess risk for cardiovascular events, contrary to common beliefs. All clinical studies performed to date with the insulin analogue detemir have shown that this analogue is associated with lesser weight gain than NPH insulin. There is no explanation yet for these intriguing results. If confirmed on the long-term, this favourable effect on weight might be an interesting feature of this new insulin analogue.

Anti-bovine serum albumin antibodies: genetic heterogeneity and clinical relevance in adult-onset IDDM.

OBJECTIVE: To evaluate the prevalence of anti-bovine serum albumin (BSA) antibodies in patients with adult-onset insulin-dependent diabetes mellitus (IDDM) and investigate a possible link between their presence and genetic susceptibility or resistance determined by human leukocyte antigen (HLA) complex. RESEARCH DESIGN AND METHODS: Sera from 60 recent-onset diabetic patients, 5 prediabetic subjects, and 102 healthy control subjects were tested using a radioimmunoprecipitation assay. HLA-DRB and -DQB alleles were determined by means of allele-specific oligonucleotide typing. Islet cell antibodies (ICAs) were assayed by indirect immunofluorescence. RESULTS: Levels of anti-BSA antibodies were significantly higher in IDDM patients (18.1 +/- 3.5%, n = 60) than in healthy control subjects (7.5 +/- 1.2%, n = 102) (P < 0.001), but in only 16.6% of IDDM patients (10 of 60) were the titers above the 95th percentile of control values. Anti-BSA antibody titers were higher in HLA-DR3 and/or -DR4 patients (23.4 +/- 4.9%, n = 41) compared with DR3 and/or DR4 control subjects (3.1 +/- 1.0%, n = 10) (P < 0.001). DR3 IDDM patients showed higher levels of anti-BSA antibodies (26.3 +/- 6.3%, n = 30) than non-DR3 patients (9.9 +/- 2.6%, n = 30) (P < 0.01) and healthy control subjects. Only two out of five prediabetic subjects had significant anti-BSA levels before clinical onset of diabetes. CONCLUSIONS: Our data confirm that antibodies to BSA are present in adult-onset IDDM patients, particularly in HLA-DR3-positive patients. However, the prevalence of anti-BSA antibodies was lower than previously reported in children, and there was a considerable overlap with healthy control subjects. Only two out of the five prediabetic patients demonstrated anti-BSA antibodies. Taken together, these results do not bring strong support to the clinical usefulness of anti-BSA antibodies as a relevant marker in diabetes prediction or diagnosis.

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.

Major histocompatibility class II genes polymorphism in insulin dependent diabetes mellitus with or without associated thyroid autoimmunity.

Insulin dependent diabetes mellitus (IDDM) is sometimes associated with extrapancreatic organ-specific autoimmune diseases, but whether this phenotype results from a peculiar genetic profile is still unclear. The allelic distribution of the major histocompatibility complex (MHC) class II genes (HLA-DRB1, DQA1, DQB1 and TAP) was analysed in 143 patients with IDDM alone by comparison with 82 IDDM patients with autoimmune thyroid disease (IDDM/AITD). The frequency of the DQB1*0301 IDDM-protective phenotype seemed to be lower in IDDM than in IDDM/AITD patients (16.8% vs 30.5% respectively, p = 0.02). By contrast, the frequency of the DRB1*04-DQB1*0302 IDDM-predisposing phenotype was higher in IDDM than in IDDM/AITD patients (91.3% vs 76.1% of DR4-positive patients respectively, p = 0.007), but these differences were not significant after correcting the p values, except in the case of the DRB1*0405-DQB1*0302 combination (21.3% vs 2.4% of DR4-positive patients, Pc = 0.05). Furthermore, all differences disappeared when patients were matched for age at IDDM-onset. Our data do not long give support for a particular role of MHC class II genes in favouring the occurrence of thyroid autoimmunity in IDDM patients, but rather suggest that some class II alleles or residues might determine the rapidity of progression to IDDM in genetically susceptible individuals. The involvement of non-MHC genes and/or environmental factors remains to be determined.

Acute renal failure in a diabetic patient.

We report the case of a young insulin-dependent diabetic patient in whom acute renal failure led to detection of ureterohydronephrosis secondary to neurogenic bladder. The persistence of a high daily urine volume revealed diabetes insipidus, suggesting Wolfram syndrome, which was confirmed by the diagnosis of optic atrophy. The main features of Wolfram syndrome, particularly urologic ones, and their treatment are discussed in the light of our findings in this patient.

[Is diabetes mellitus a sufficient condition to suspect hemochromatosis?]. / Faut-il rechercher une hémochromatose lors de la découverte d'un diabète ?

Genetic Hemochromatosis (GH) is a highly prevalent autosomal recessive disorder, which outcome has been dramatically improved by early phlebotomy. Attempts to screen for the disease, using biological and genetic approaches, are currently under evaluation. Diabetes mellitus often complicates GH. However, as it occurs late in the course of the disease, in most cases when cirrhosis is already present, its usefulness for the screening of GH seems reduced. Diabetes mellitus, when isolated, appears also as a poor predictor of hemochromatosis. Indeed, the risk of being carrier of the disease is not increased in diabetic patients compared with non diabetic sujects. This risk is however highly enhanced by the co-existence of cirrhosis. Thus, in the face of a newly diagnosed diabetes mellitus, the search for hemochromatosis must be performed only when it associates with cirrhosis or with other evocative clinical conditions.

[Insulin sensitivity, blood pressure and cardiovascular diseases]. / Insulinosensibilité, pression artérielle et maladies cardiovasculaires.

Essential hypertension is one of the main components of the insulin resistance syndrome. Blood pressure levels are especially critical for the cardiovascular prognosis of patients with diabetes. However, whether the relationship between blood pressure levels and insulin sensitivity is causal, or just an association, remains debatable. In this study, this relationship is explored through the data of currently available clinical trials.

[Insulin and weight gain: myth or reality?]. / Insuline et prise de poids mythe ou réalité?

Most patients with type 2 diabetes gain weight when treated with insulin. Weight gain is observed when insulin is introduced after oral agents have failed, but also when insulin is introduced shortly after the diagnosis of diabetes. The mechanisms of this weight gain are incompletely understood, but reduction of energy lost by glucosuria and reduction of energy needed for glucose production are main determinants. The same reasons apply to the weight gain observed at the beginning of treatment with sulfonylureas, even though patients usually gain less weight with sulfonyulreas than with insulin. In the UKPDS, at 10 years of the study, patients treated with insulin gained 2 kg more, i.e. 2.5% of the average weight of patients included in the trial, than patients treated with sulfonylureas. The reasons of the excess of weight gain with insulin as compared with sulfonylureas remain unclear. Patients with type 2 diabetes treated with insulin gain weight only during the first 2-3 years after insulin introduction. The weight stabilizes thereafter. Type 2 diabetes usually remains unknown for years before diagnosis and patients may lose weight during this long period of time preceding diagnosis. It is hypothesized that the weight gain observed after the introduction of insulin may simply correspond to the reexpression of the physiologically controlled body weight.

[Insulin-dependent diabetes and organ specific autoimmune diseases: a retrospective clinical and immunogenetic study of 165 consecutive cases]. / Diabète insulino-dépendant (DID) et maladies auto-immunes spécifiques d'organe (MAIS): une étude clinique et immunogénétique rétrospective de 165 cas consécutifs.

We analysed clinical and immunological indexes in 165 caucasian adult patients presenting insulin-dependent diabetes mellitus associated with other organ-specific autoimmune diseases (type Ib IDDM). As diagnostic strategy, we recommend testing thyrogastric autoantibodies at diabetes onset and islet-cells antibodies three years after.