Insulin-deficient Patients Research Articles

Single-Cell RNA-seq Analysis Reveals a Positive Correlation between Ferroptosis and Beta-Cell Dedifferentiation in Type 2 Diabetes.

Insulin deficiency in patients with type 2 diabetes mellitus (T2D) is associated with beta-cell dysfunction, a condition increasingly recognized to involve processes such as dedifferentiation and apoptosis. Moreover, emerging research points to a potential role for ferroptosis in the pathogenesis of T2D. In this study, we aimed to investigate the potential involvement of ferroptosis in the dedifferentiation of beta cells in T2D. We performed single-cell RNA sequencing analysis of six public datasets. Differential expression and gene set enrichment analyses were carried out to investigate the role of ferroptosis. Gene set variation and pseudo-time trajectory analyses were subsequently used to verify ferroptosis-related beta clusters. After cells were categorized according to their ferroptosis and dedifferentiation scores, we constructed transcriptional and competitive endogenous RNA networks, and validated the hub genes via machine learning and immunohistochemistry. We found that ferroptosis was enriched in T2D beta cells and that there was a positive correlation between ferroptosis and the process of dedifferentiation. Upon further analysis, we identified two beta clusters that presented pronounced features associated with ferroptosis and dedifferentiation. Several key transcription factors and 2 long noncoding RNAs (MALAT1 and MEG3) were identified. Finally, we confirmed that ferroptosis occurred in the pancreas of high-fat diet-fed mice and identified 4 proteins (NFE2L2, CHMP5, PTEN, and STAT3) that may participate in the effect of ferroptosis on dedifferentiation. This study helps to elucidate the interplay between ferroptosis and beta-cell health and opens new avenues for developing therapeutic strategies to treat diabetes.

A Re-audit of the Management of Diabetic Ketoacidosis (DKA): The Importance of the Seven-Day Working Inpatient Diabetes Specialist Nurse Service.

Background Diabetic ketoacidosis (DKA) is a life-threatening metabolic emergency due to insulin deficiency in patients with diabetes mellitus. The United Kingdom national survey and local audits of the management of DKA have revealed several areas of suboptimal care, and room for improvement, necessitating the need for intensified education, updating local guidelines, and increased recruitment of seven-day working inpatient diabetes specialist nurses. Therefore, this project aimed to re-audit our adherence to the DKA treatment guidelines. Methodology A retrospective re-audit examining patient admissions with DKA between October 2022 and September 2023. A list of 18 standards/criteria, adopted from the Joint British Diabetes Society (JBDS) DKA treatment guidelines was used for this re-audit. Results were compared with that of the previous audit. Results We had 126 patients admitted with DKA between October 2022 and September 2023. There were 62 males and 64 females with an average (range) age of 46.5 (19-92) years. Eighty percent had type 1 diabetes, and common precipitating factors for admission included infection and poor adherence to insulin treatment. The median (IQR) length of hospital stay was 2.1 (1.0-5.1) days. Compared to the previous audit, improvements occurred in 11 of 18 standards/criteria. This included timely commencement of intravenous fluids and fixed-rate insulin, commencing glucose infusion to prevent hypoglycemia,potassium replacement, continuation of long-acting insulin during treatment, timely conversion to variable-rate insulin infusion, and conversion to the usual subcutaneous insulin regimen. Additionally, 124 patients (98.4%) were reviewed at least once by the inpatient diabetes specialist nurses (DSN) during their admission. Complications of treatment, namely, iatrogenic hypoglycemia and transient hypokalemia occurred in 13 (10.3%) and 40 (31.7%) patient admissions, respectively. Conclusions This re-audit demonstrated improved adherence to the guidelines during several steps in the management of DKA. It also demonstrated room for improvement regarding other aspects of care. The importance of continued education, accurate documentation, and the presence of seven-day working inpatient DSN cover cannot be overemphasized.

Lipid variability in patients with diabetes mellitus

Diabetic dyslipidemia is characterized by hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), elevated low-density lipoprotein cholesterol (LDL-C), and the predominance of small dense LDL particles caused by insulin resistance in patients with type 2 diabetes mellitus (DM) or insulin deficiency in patients with type 1 DM. Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease in individuals with DM, and lowering lipid levels can reduce the associated morbidity and mortality. The current guidelines for dyslipidemia management recommend an LDL-C goal lower than 55 to 100 mg/dL, depending on the underlying risk factors. However, greater visit-to-visit variability in cholesterol levels might be an independent predictor of major adverse cardiovascular events, high incidence of atrial fibrillation, poor renal outcomes, and cognitive dysfunction in patients with DM. This review focuses on the clinical implications of lipid variability in patients with DM.

Phenolic Profiles, Antihyperglycemic, Anti-Diabetic, and Antioxidant Properties of Egyptian Sonchus oleraceus Leaves Extract: An In Vivo Study.

This study aimed to investigate the phenolic and antioxidant properties of Egyptian Sonchus oleraceus leaves extract (SOE) while comparing the antihyperglycemic efficacy of SOE with that of conventional medicines (glibenclamide) in vivo as a substitution for insulin-deficient patients. Total phenolic (TPC) and flavonoid contents (TFC) in SOE contributed around 127.66 ± 0.56 mg GAE/gm as gallic acid equivalent (GAE) and 74.80 ± 0.55 mg QE/gm as quercetin equivalent (QE). SOE also showed significant DPPH scavenging activity at 43.46%. The presence of five phenolic and six flavonoid compounds in SOE was discovered by HPLC analysis. For the in vivo assay, 42 rats were distributed into six groups (7 Wister albino rats each). The standard control group was fed a basal diet. While the 35 rats were induced with a single dose of 100 mg kg-1 body weight (b.w.) alloxan, then treated orally with glibenclamide (GLI) at 10 mg kg-1, 100, 200, and 300 mg kg-1 SOE (positive control group) for 56 days of routine gastric oral gavages and compared to the effects of GLI, the treatment of SOE 200 and 300 mg kg-1 in diabetic rats for two months dramatically decreased blood glucose, total lipid, total cholesterol, and low-density lipoprotein cholesterol (LDLC) while boosting high-density lipoprotein cholesterol (HDLC) levels and improving liver and kidney functions. The histological assay revealed that the SOE 300 mg kg-1 treatment significantly improved the pancreas tissues, implying the potential application of Egyptian SOE as a diabetes treatment.

Disruption of the dopaminergic system in the pathophysiology of diabetes mellitus

Introduction. Diabetes mellitus (DM) is the most common endocrinopathy with a high incidence and a high number of complications.The aim of this work was to conduct an analytical literature review assessing the state of the problem of dopaminergic dysfunction in diabetes from a pathophysiological perspective.Materials and methods. Searching Cochrane Library, PubMed, eLibrary, Medscape databases and digital libraries using the search words: diabetes mellitus, dopamine, insulin, dopaminergic system, diabetic encephalopathy. A total of 66 sources were selected for the review.Results and discussion. Dopaminergic system dysfunction can be considered an important component of the pathophysiology of diabetes. Hyperactivation of dopamine (DA) production in the setting of diabetes inhibits insulin synthesis, resulting in hyperglycemia. On the other hand, hypoinsulinemia triggers activation of the dopaminergic system, forming a vicious circle. Increased DA production in diabetes plays an important role in the development of secondary central nervous system dysfunction, primarily through the development of cerebral insufficiency. Numerous preclinical studies confirm the dysfunction of the dopaminergic system (its activation) in diabetes. Clinical studies on this issue are scarce and require further investigation.Conclusion. Dysfunction of the dopaminergic system in diabetes is an important area of research into the pathophysiology of symptomatic neurological disorders in this disease. Type 1 and type 2 diabetes are pathogenetically different diseases, and therefore impaired DA production may be due to insulin deficiency in patients with type 1 diabetes, different timing of manifestation, with hyperinsulinemia and insulin resistance in type 2 diabetes. Finding reliable methods to diagnose dysfunction of the dopaminergic system may improve understanding of the ongoing pathological processes in the neuroendocrine system in diabetes, which is important in addressing their correction in addition to pathogenetic therapy.

Common metabolic features of hypertension and type 2 diabetes.

Hypertension and type 2 diabetes frequently coexist, suggesting that the two diseases have common pathophysiological bases. This review describes the pathophysiological mechanisms of how type 2 diabetes is frequently associated with hypertension. Multiple common factors mediate between both diseases. Factors that induce both type 2 diabetes and hypertension include obesity-induced hyperinsulinemia, activation of the sympathetic nervous system, chronic inflammation, and changes in adipokines. Vascular complications resulting from type 2 diabetes and hypertension include endothelial dysfunction, vasodilation/constriction dysfunction of peripheral vessels and increased peripheral vascular resistance, arteriosclerosis, and chronic kidney disease. While many of these vascular complications are caused by hypertension, they also exacerbate the pathology of hypertension. In addition, insulin resistance in the vasculature blunts insulin-induced vasodilation and blood flow to skeletal muscle, which contributes to impaired glucose uptake to skeletal muscle and glucose intolerance. In obese and insulin-resistant patients, increase in the circulating fluid volume forms the major pathophysiology of elevated blood pressure. On the other hand, in non-obese and/or insulin-deficient patients, especially those in the middle- or later stages of diabetes, peripheral vascular resistance is the major pathophysiology of hypertension. The relationship between various factors involved in the pathogenesis of type 2 diabetes and hypertension. It should be noted that all the factors shown in the figure are not necessarily present simultaneously in every patient.

1247-P: Subgroup Analysis of Diabetic Patients Living in Tibet Plateau

Background: recently, a novel subgroups of adult-onset diabetic patients has been reported. Their work implied that type 2 diabetic patients can be classified into four groups. However, the utility of this classification method in Tibet populations and the clinical character of each cluster of Tibetan patients is unknown. Methods: this is a cross-sectional study, patients newly diagnosed with type 2 diabetes was analyzed. Data was collected from hospital information system (HIS) , and homoeostasis model assessment 2 of β-cell function (HOMA2-B) and insulin resistance (HOMA2-IR) was calculated using fasting glucose and fasting C-peptide by HOMA calculator. The age at onset of diabetes, Hba1c, BMI, HOMA2-B and HOMA2-IR was used for clustering. K-means cluster method was used with k value of 4. The stability of each cluster was assessed by resampling the dataset and computing Jaccard similarities. All statistical analysis was performed on R and fpc package. Result: A total of 581 patients was enrolled, the four clusters with similar clinical aspect is observed in Tibetan population and the average jaccard similarities is over 0.7. The same as Ji's result, the largest subgroup is mild age-related diabetes cluster (MARD) 255 out of 581 (44.3%) patients is classified into this cluster. And 147 (25.6%) patients is classified into mild obesity related diabetes (MOD) . The proportion of severe insulin- resistant related diabetes (SIRD) (1.4%) is lower and those of severe insulin-deficient related diabetes (SIDD) (28.7%) is higher compared to Ji's study. This result implies that there may be more severe insulin-deficient patients and less severe insulin-resistant patients in Tibet plateau. Discussion: in this study, we found out that the cluster method developed by Emma Ahlqvist is suitable for Tibetan population, compared to the rest Chinese population, there're more severe insulin-deficient patient, and less severe insulin-resistance patients. Disclosure W.Suyuan: None. C.Zhang: None.

Glycaemic control in insulin deficient patients using different insulin delivery and glucose sensoring devices: Cross-sectional real-life study

AimsTo assess glycaemic control in ≥15-year-old patients with type 1 diabetes treated in Tampere University Hospital in a real-life cross-sectional registry study. MethodsGlycaemic control was assessed with HbA1c, time in range (TIR) and the incidence of acute complications. The effect of age, BMI, gender, duration of diabetes, daily insulin dose, and device group on the glycaemic control was studied. ResultsThe study included 1,132 patients. Eighty-four percent of the patients had TIR≤70%. Two percent of patients had an episode of diabetic ketoacidosis and 0,2% had severe hypoglycemia within the last 12 months. Intermittently scanned CGM (IsCGM) with MDI was used in 59%, continuous subcutaneous insulin infusion (CSII) with glucose sensor in 15%, and sensor-augmented/hybrid closed-loop pump (SAP/HCL) in 9% of the patients. In the logistic regression analysis, TIR≤70% was associated with young age group (OR 2.70; 95% CI 1.43–5.09) and daily insulin dose per weight (OR 6.66; 95% CI 3.53–12.57). CSII with glucose sensor and IsCGM with MDI were associated with poor glycaemic control compared to SAP/HCL. ConclusionThere is room for improvement in the glycaemic control in our area although serious acute complications are rare. Closed insulin pump system was more effective than open system.

The evaluation of early stage oxidative status in streptozotocin induced diabetes in rats

Early-stage diabetes can be defined as the stages before absolute insulin deficiency in patients. In this study, the early stage oxidative effect of streptozotocin(STZ) induced diabetes mellitus was evaluated. 28 male adult Sprague-Dawley rats were divided into four groups; control group and 7th, 14th, 21st days diabetic groups. Diabetic groups received single 65 mg/kg STZ injection intraperitoneally. Rats were decapitated at 7th, 14th and 21st days, liver tissues were taken. Nitric oxide(NO), malondialdehyde(MDA) levels and catalase, arginase activities were measured. MDA and NO levels were increased (respectively p < .001 and p < .01), mainly 14 and 21 days after STZ administration; moreover, while liver catalase activity was progressively decreased (p < .001), oppositely arginase was increased in the same time period (p < .01). Results show that MDA and nitric oxide together with catalase and arginase switch at an early stage of diabetes and they may contribute to subsequent complications related to diabetes via increased oxidative damage.

1513-P: The Severe Insulin-Resistant Diabetes Cluster Features Higher Liver Fat Content, but Also an Accelerated Risk of Liver Fibrosis over Five Years after Diagnosis

Cluster analysis using age, BMI, glycemia and homeostasis model estimates (HOMA-IR, -B) revealed distinct risk profiles for progression of diabetic nephropathy in large cohorts, but its relevance for other diabetes-related comorbidities remains unclear. We aimed to (i) examine whether intensified phenotyping would confirm the results of this cluster analysis and (ii) test the hypothesis that liver fat content (HCL), as marker of nonalcoholic fatty liver disease (NAFLD), differs among clusters at diabetes diagnosis and during follow-up. Thus, this cluster analysis was applied to recent-onset patients with non-autoimmune diabetes of the German Diabetes Study. This identified 286 mild age-related (MARD, 44%), 268 mild obesity-related (MOD, 42%), 66 severe insulin-resistant (SIRD, 10%) and 27 severe insulin-deficient (SIDD, 4%) diabetes patients. Furthermore, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps, HCL by magnetic resonance spectroscopy and hepatic fibrosis by a noninvasive score (NAFLD-FS). Congruently, whole-body insulin sensitivity was lowest in SIRD compared to MOD, SIDD and MARD (4.3±2.0 vs. 5.6±2.4, 6.5±2.6, 7.6±2.8 mg*kg-¹*min-¹, all p&amp;lt;0.05). In SIRD, HCL (14±4%) was higher than in SIDD (5±2%), MOD (9±1%) and MARD (7±1%) (all p&amp;lt;0.05). In SIRD, HCL negatively correlated with whole-body insulin sensitivity (r=-0.27, p&amp;lt;0.05). NAFLD-FS was highest in SIRD (0.4) compared to SIDD (-2.9), MOD (-0.8) and MARD (-0.8) (all p&amp;lt;0.05). At the 5-year follow-up (n=159), whole-body insulin sensitivity remained lowest in SIRD (p&amp;lt;0.05 vs. all clusters) with no difference in changes between clusters. Also, significant fibrosis (NAFLD-FS &amp;gt;0.6) was highest in SIRD (21%) compared to SIDD (0%), MOD (16%) and MARD (11%). In conclusion, patients of the SIRD cluster exhibit higher prevalence of steatosis at diagnosis and increased risk of NAFLD progression over 5 years. Disclosure O.P. Zaharia: None. K. Strassburger: None. Y. Kupriyanova: None. Y. Karusheva: None. S. Antoniou: None. K. Bodis: None. O. Asplund: Research Support; Self; Eli Lilly and Company. V. Burkart: None. K. Muessig: None. J. Hwang: None. O. Kuss: None. L. Groop: None. E. Ahlqvist: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. Funding German Ministry of Culture and Science of the State of North Rhine-Westphalia; German Federal Ministry of Health; German Federal Ministry of Education and Research

Excess mortality in diabetic subjects due to alcohol, accidents and suicide: A nationwide cohort study

Introduction Patients with diabetes mellitus are known to have markedly higher mortality due to cardiovascular diseases, cancer and renal causes, whereas the mental strains imposed by chronic diseases and substance abuse as well as the accidental causes of excess mortality have gained relatively little attention. Mental symptoms and diseases are common among diabetic patients, such as depression and suicidal ideation. A recent meta-analysis [1] found that diabetes was associated with a significantly increased risk of suicide, especially in insulin-deficient (type 1) diabetic patients. Methods We have analyzed the intertwined external causes of death due to alcohol-related causes, accidents and suicides in a large national cohort containing all the patients treated with insulin and a random sample of half of those treated with oral antidiabetic drugs as being matched with a reference population. The study population was constructed based on the data of CARING Project [2] in Finland ( http://www.caring-diabetes.eu/ ). The study population consisted of 475,360 individuals, 220,110 men and 206,472 women. We used suicides and sequelae of intentional self-harm, accidents, and alcohol-related diseases and accidental poisoning by alcohol as the endpoint events. We categorized subject into four groups by the diabetes drug at the start of the follow-up: no DM (reference), only oral antidiabetic drugs (OAD), OAD and insulin, and only insulin. The following variables were adjusted for age, calendar year in start of follow-up, usage of statins, usage of HRT, time since start of follow-up, cancer before start of follow-up, and hospital district. Adjusted mortality rate ratios (MRR) were estimated using Poisson regression model. Separate models were calculated for men and women. Results The mean follow-up time was 6.6 years and 2.8 million person-years were cumulated during follow-up. We observed 2716 deaths caused due to alcohol-related causes, 3220 due to accidents, and 832 due to suicides. All diabetic groups, both men and women, had higher risk of alcohol-related death. Risk was high especially in insulin group, with MRR for men 4.56 (95% CI: 4.12, 5.05) and for women 4.32 (2.99, 6.24). Similar pattern was observed in accidents. MRR varied between men with OAD only group 1.16 (1.03, 1.30) and women in insulin only group 1.71 (1.47, 1.98). Also risk of suicide were higher in diabetics with highest MRR 2.04 (1.48, 2.81) in women in OAD only group. Conclusions To conclude, we found in this large nationwide cohort that diabetic patients showed higher mortality due to suicides, alcohol-related causes and accidents than nondiabetic population, and that this premature mortality was most clearly associated with the use of insulin, reflecting the severity of diabetes, and with male gender. These findings underscore the importance of identifying high-risk patients early enough as well as effective psychosocial support and interventions among these individuals.

Insulin degludec is associated with less frequent and milder hypoglycemia in insulin-deficient patients with type 1 diabetes compared with insulin glargine or detemir.

The aim of this study was to determine the efficacy of insulin degludec (IDeg) relative to insulin glargine (IGlar) or insulin detemir (IDet) in glycemic control, as evaluated by continuous glucose monitoring (CGM) in insulin-deficient patients with type 1 diabetes. We studied 28 outpatients treated with IGlar or IDet (IGlar/IDet). Basal insulin was switched to IDeg when glycemic control was considered unstable, as judged by the dawn phenomenon or nocturnal hypoglycemia. Whole-day CGM data were also divided into daytime and nighttime data. The dawn phenomenon or nocturnal hypoglycemia under IGlar/IDet treatment was observed in all patients. Among 26 patients who completed the study, there were no significant differences in parameters representing glycemic variability, hyperglycemia, mean glycemic control, and HbA1c or insulin therapy-related quality of life at the night score. Measures of hypoglycemia [whole-day %Low and area under the curve (AUC) below 70] were significantly lower under IDeg treatment than under IGlar/IDet treatment (%Low, 9.6±11.5 vs. 14.7±14.9%, p=0.045; AUC below 70, 85.5±126.0 vs. 145.0±178.6mg/dlh, p=0.030). Dividing patients into two groups according to percentage or degree of hypoglycemia under IGlar/IDet treatment, the whole-day, daytime and nighttime %Low in the high-percentage groups and AUC below 70 in the high-degree groups were significantly ameliorated, respectively (p<0.05). Patients with unstable glycemic control under IGlar/IDet treatment did not improve glycemic control upon switching to IDeg, but the frequency and the degree of hypoglycemia was reduced in insulin-deficient outpatients with type 1 diabetes, especially in those suffering from severe hypoglycemia.

The importance of beta cell characterisation: generating human beta cells by differentiating human embryonic stem cells

Exogenous insulin administration continues to be the most common means of correcting the absolute insulin deficiency in patients with type 1 diabetes mellitus. Nevertheless, the best available insulin therapy does not control blood glucose levels in a physiological manner, leading to several serious metabolic and neurovascular complications [1]. Beta cell replacement offers an attractive alternative, potentially enabling precise glycaemic control. Clinical islet transplantation, for instance, has proven effective in improving glucose homeostasis, reducing episodes of hypoglycaemia and achieving insulin independence [2]. However, the shortage of donor islet tissues is a major restriction for widespread application of beta cell replacement therapies. The recent developments in stem cell research suggest that human embryonic stem cells (hESCs) hold great promise for fulfilling this need for an unlimited supply of readily available insulin-producing cells. Embryonic stem cells are pluripotent cells derived from the inner cell mass of blastocysts. They exhibit the capacity to develop into the three embryonic germ layers (endoderm, mesoderm and ectoderm). To generate beta cells from hESCs, current approaches have been guided by knowledge of pancreatic development. By recapitulating these developmental signals, several groups have been able to differentiate hESCs into insulinpositive cells [3–6]. Jiang et al. utilised a differentiation protocol omitting serum from the culture medium and reported the presence of islet-like clusters that secreted Cpeptide in response to glucose [3]. However, C-peptidepositive cells only accounted for 2–8% of all cells in the islet-like cluster [3]. When transplanted into chemically induced diabetic mice, the islet-like clusters prolonged survival and secreted C-peptide in response to a glucose challenge [4]. Novocell (now known as ViaCyte, San Diego, CA, USA) developed another differentiation protocol in which hESC-derived insulin positive cells could secrete C-peptide but only in the presence of secretagogues like KCl [5]. When hESC-derived pancreatic progenitors were transplanted into athymic mice, they reported that these cells could also produce human insulin and C-peptide levels comparable to 3,000 human islets [6]. While the results reported by the ViaCyte group were impressive, Matveyenko et al. had difficulty replicating these results in athymic rats [7]. In addition, the recipient mice responded poorly to glucose tolerance testing, which suggests that insulin secretion was not glucose dependent. Clearly, improvements to directed differentiation attempts are necessary to overcome two significant hurdles that G. S. Korbutt : T. Y. Yeung :C. E. Ellis Department of Surgery, Alberta Diabetes Institute, Edmonton, AB, Canada

Effect of human leukocyte antigen class II genes on insulin deficiency in slow-onset type 1 diabetes in the Japanese population

The aim of this study is to determine the contribution of human leukocyte antigen (HLA) class II genes to insulin deficiency in slow-onset type 1 diabetes (T1D). Our results suggest that the susceptibility conferred by HLA subtypes to slow-onset T1D differs between insulin-deficient patients and non-insulin-deficient patients.

Polymorphisms of Superoxide Dismutase, Glutathione Peroxidase and Catalase Genes in Patients with Post-transplant Diabetes Mellitus

Post-transplant diabetes mellitus (PTDM) is a metabolic disorder that develops in response to a relative insulin deficiency in patients after organ transplantation treated with immunosuppressive drugs. Several studies have suggested that oxidative stress may be associated with diabetes and its complications. The aim of this study was to examine the association of polymorphisms in superoxide dismutase, catalase and glutathione peroxidase genes with PTDM in patients after kidney transplantation. The study included 159 patients receiving kidney transplants. PTDM was diagnosed in 21 patients. Analyzing the C599T (Pro200Leu) polymorphism in the GPX1 gene PTDM was diagnosed in 8.45% of patients with CC genotype, 13.43% with CT and in 28.57% with TT. Allele T was significantly more frequent among patients with PTDM compared to patients without PTDM (OR = 2.14, 95% CI = 1.11-4.12, p = 0.024). There were no associations between SOD1, SOD2 and CAT polymorphisms and PTDM. The present results suggest that Pro200Leu polymorphism of the GPX1 gene may be associated with the risk of PTDM development in renal graft recipients.

Genetic markers in diabetes mellitus: the need and promise for specific drug therapies in defined subtypes of diabetes patients

frequency or severity of hypoglycemia. Further benefit is often attained from additional treatment directed to normalizing blood pressure and circulating lipids, as well as specific interventions for diabetes complications, such as laser therapy for retinopathy. This article will focus on current approaches to blood glucose control. The management of glycemia in diabetes typically includes attention to diet and exercise combined with pharmacologic agents selected from a palette of injectable and oral drugs. Advances in available forms of insulin and other drugs over the past two to three decades, plus home glucose meters and, for some patients, devices such as insulin pumps and continuous glucose monitoring systems, has substantially increased the capacity of diabetes patients to control their blood glucose levels and to decrease the associated long-term risks. However, current therapeutic strategies still often fail to bring patients to glycemic targets. In the USA, data from the National Health and Nutrition Examination Survey (NHANES) indicates that only approximately 50% of diabetes patients are at or below the conservative hemoglobin A1c goal of 7% [2]. In considering strategies for improving glycemic therapy, there is increasing interest in approaches that better link treatment to specific diabetes subtypes in individual patients. It has long been known that diabetes is a heterogeneous disorder. Recognition of different forms of the disease corresponding to today’s Type 1 and 2 diabetes is evident in medical writing dating back 2000 years [3]. Standard treatment approaches to these two forms of diabetes differ, with early initiation of insulin in patients recognized to have Type 1 diabetes and often long periods of management with oral hypoglycemic agents in patients with Type 2 diabetes. More refined examination of individual phenotypes, biochemical markers, and inheritance patterns over the past several decades has progressively identified additional diabetes subtypes, such as maturity onset diabetes of the young (MODY), An estimated 24 million people in the USA (>8% of the population) and approximately 250 million people worldwide have diabetes [101]. When it is poorly controlled, diabetes has acute medical consequences resulting from osmotic diuresis, disturbed fluid and electrolyte balance, compromised immune function and, in extremely insulin-deficient patients, ketoacidosis. Of equal or greater importance, the diagnosis of diabetes brings with it a markedly increased risk of longterm complications. Diabetes-associated macrovascular disease contributes to an increased occurrence of myocardial infarction, congestive heart failure, stroke and peripheral vascular disease, and microvascular complications of diabetes often lead to loss of vision, renal insufficiency and disabling symptomatic neuropathies. In the USA, diabetes is the seventh leading cause of death, largely from the impact of its long-term complications, with financial costs that exceed US$150 billion per year [101]. The development of diabetes in most individuals results from an unfavorable confluence of environmental and genetic factors. In Type 1 diabetes, it is thought that yet unidentified environ mental insults (toxic, infectious or other), acting in a susceptible genetic background, lead to initiation and progression of autoimmune b-cell destruction. In Type 2 diabetes, lifestyle factors (excess calorie intake, decreased exercise and possibly specific dietary components), again acting in a susceptible genetic background, typically result in both insulin resistance and compromised insulin secretion. The common defining biomarker for diabetes is hyperglycemia and, irrespective of the underlying cause, compelling data indicate that improved control of blood glucose in diabetes relieves acute symptoms, reduces long-term complications, and decreases associated morbidity and mortality. Although there is ongoing debate on the preferred target level for glycemia [1], the accepted fundamental principle is one of bringing blood glucose as close as possible to normal without inducing an unacceptable

Thinking Like a Pancreas: Perioperative Glycemic Control

Peter J. Pronovost, MD, PhD*† Perioperative glycemic control is related to patient outcome. Although guidelines for glucose management in hospitalized patients have undergone dramatic changes over the last 5 years, most hospital-based physicians, including anesthesiologists, have not changed their approach to glucose management (1). In this editorial, we discuss the article by Duncan et al. (2) appearing in this issue of Anesthesia & Analgesia, review recent recommendations for perioperative glucose management, and highlight areas of uncertainty. We endeavor to improve perioperative glucose management for patients. There is considerable uncertainty regarding how to manage surgical patients who are taking metformin, an oral hypoglycemic drug. The potential for postoperative lactic acidosis in patients taking this drug has prompted some clinicians and health care systems to routinely cancel surgical procedures if metformin is taken within 48 h of surgery. Other clinicians or health care systems continue metformin, both before and after the surgical procedure. Duncan et al. (2) conducted a retrospective review of a large cohort of diabetic patients admitted for cardiac surgery at their institution who recently took an oral hypoglycemic drug. They compared outcomes among patients who took metformin versus patients taking a non-metformin oral hypoglycemic drug. The authors found that patients taking metformin had lower risks for several complications, and concluded that metformin appeared to be safe for use in the perioperative period. The article raises several points worthy of reflection. First, the authors used a propensity score to try to account for differences among patients who were taking, versus not taking, metformin. This statistical method used logistic regression, in which metformin becomes the dependent variable. Predictor variables are included in the model (in this case 54 variables) to identify those patient characteristics associated with metformin treatment. The output of this analysis includes a C statistic that is interpreted to mean that, for any given pair of patients, in which one patient received metformin and one did not, how often did the model identify the one receiving metformin? In this analysis, the C statistic was 0.68, suggesting that more than 3 of 10 patients were not correctly classified. Thus, there is the potential that unmeasured differences between groups, and not metformin treatment or nontreatment, could influence the results. Other evidence suggests that propensity scores are no better than standard regressions at controlling for selection bias (3). Second, the authors evaluated a variety of outcomes, though many were uncommon and did not include explicit definitions, and concluded that metformin was safe. It would be helpful to consider the precise safety of these estimates (3). For example, even if none of the 523 metformin patients had an adverse event in this study, the upper limit of that confidence interval is seven events in 1000 patients. This rate would likely warrant concern from clinicians and lead to alterations of their practice. Rather than thinking of drug safety as a dichotomous variable, (i.e., safe versus unsafe) it may be helpful to think of safety as a continuous variable to help regulators, clinicians, and consumers make a more informed risk/benefit assessment. From the Departments of *Anesthesiology and Critical Care Medicine and †Surgery, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Accepted for publication October 26, 2006. Conflicts of Interest: Dr. Martinez has agreed to be a consultant for Bay City Capital LLC, but has not received any compensation as of this submission. The authors have no other potential conflicts of interest to disclose. Reprints will not be available from the authors. Address correspondence to Elizabeth A. Martinez, MD, MHS, ACCM/Adult Critical Care Division, 600 N. Wolfe St., Meyer 296, Baltimore, MD 21287. Address e-mail to emartine@jhmi.edu. Copyright © 2006 International Anesthesia Research Society DOI: 10.1213/01.ane.0000252348.81206.7f

La Suppléance Insulinique : nouvelles insulines, nouveaux procédés d'administration

The demonstrated role of the tight control of hyperglycaemia for the prevention of long-term diabetic complications has reoriented the goals of insulin supply toward the search for restoration of the effects of physiological insulin secretion rather than the simple survival of insulin deficient patients and the reduction in the number of daily insulin injections to be performed. Normal blood glucose control requires the availability of a fast-acting insulin therapy at meal time in order to reduce hyperglycaemic excursions and a basal insulin therapy able to stabilize blood glucose between meals. Reduction of induced hypoglycaemic risk represents the secondary objective beside the main goal of avoiding hyperglycaemia. Fast-acting analogues, by a faster dissociation of their hexameric conformation after their injection or infusion in subcutaneous tissue, reduce post-meal hyperglycaemia, while their shortened duration of action versus regular insulin minimizes late post-absorptive risk of hypoglycaemia. Long-acting analogues, by their precipitation in subcutaneous tissue or their slowly reversible binding to albumin, provide a benefit on blood glucose stability versus NPH or zinc insulins. Continuous insulin therapy using pumps offers both a better blood glucose stability than multiple daily injections and a broader flexibility in life mode. Using the peritoneal route by implantable pumps is a mean to improve blood glucose stability in poorly controlled patients in spite of optimized subcutaneous insulin therapy. The development of glucose sensors provides reinforced information on blood glucose, versus self-monitoring by capillary blood measurements, that contributes to a better adaptation of insulin therapy. First trials of connections between blood glucose data and insulin delivery open a perspective toward glucose-modulated insulin therapy, at least in periods outside meals, leading to first models of semi-automated artificial endocrine pancreas. The alternative of a cellular insulin supply by pancreas or islet transplantation looked promising during recent years, but lack of transplants and adverse events related to immune suppression limit their use to very specific cases where benefit/risk ratio is positive.

Clinical and genetic characteristics of diabetic patients with high-titer (>10,000 U/ml) of antibodies to glutamic acid decarboxylase

We investigated the clinical aspects and genetic background of 13 diabetic patients with high-titers (>10,000 U/ml) of anti-glutamic acid decarboxylase antibody (Group A) and compared these 28 middle-aged (35–51 years, Group B) and 13 elderly (66–79 years, Group C) patients with anti-GAD + (<1100 U/ml) who were diagnosed initially as having type 2 diabetes. The mean age and mean age at onset of Group A were 70.8 ± 3.9 years (range, 64–78) and 50.4 ± 5.4 years (range, 43–61), respectively. In Group A, the prevalence of insulin-deficient patients was significantly lower (30.8%, 4 of 13) than in Group C (96.3%, 27 of 28, P < 0.001). Patients in Group A had a significantly longer interval between the clinical onset of diabetes to initiation insulin therapy (21.8 ± 2.3 years) compared to patients in both Group B (1.8 ± 1.1 years, P < 0.001) and Group C (14.8 ± 7.1 years, P = 0.049). The frequency of DRB1*0405-DQB1*0401/DRB1*1502-DQB1*0601 or DRB*1501-DQB*0602 heterozygous genotypes in Group A (53.8%, 7 of 13) was significantly higher than in both Group B (3.6%, 1 of 28, P < 0.01) and Group C (7.7%, 1 of 13, P < 0.05). Compared with Group B, Group A had an increased frequency of the TNFA-U01 haplotype and the IL-10 − 592 C allele ( TNFA-U01; 53.8% versus 30.4%, P = 0.05 and IL-10 − 592 C; 57.7% versus 33.9 %, P = 0.042). All sera from Group A reacted with GAD 65 protein on Western blots. We conclude that adult-onset diabetic patients with a high-titer of anti-GDAab differ from patients with latent autoimmune diabetes mellitus in adult (LADA) with respect to β-cell function, cellular autoimmunity and genetic background. Our study also showed that high-titers of antibodies to glutamic acid decarboxylase (anti-GADab) were not predictive of later development of insulin deficiency in adult and/or elderly patients with type 2 diabetes. Furthermore, our results suggest that HLA-DRB1*1502-DQB1*0601 or DRB1*1501-DQB1*0602/DRB1*0405-DQB1*0401 heterozygous genotypes may be associated with high production of anti-GADab that recognizes the linear epitope(s) on the GAD 65 protein.

What are capillary blood ketone levels in type 1 diabetic patients using CSII in normal conditions of insulin delivery?

The aim of the study was to determine the normal level of capillary ketonemia in type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII). A total of 36 type 1 diabetic patients treated by external pump were studied for 2 to 3 weeks. Patients were instructed to self monitor capillary glucose and capillary ketone bodies at least 4 times per day with a handheld Medisense Optium meter and check for urinary ketone bodies in the morning and when blood glucose exceeded 2.5 g/l with a semiquantitative test. Data were collected and analysed for each period of time defined as the time interval between two changes of the infusion site. A period was considered "normal" when no problem causing any impairment in insulin delivery was detected. 186 periods of 2.1 +/- 0.9 days were recorded; 119 were considered normal. 1281 coupled values of glucose and betahydroxybutyrate were analysed during the so called normal periods. Mean percentage of ketonemia of 0, 0.1, 0.2, > or =0.3 mmole/l were 81.3%, 13%, 3.7% and 2% respectively whereas mean glucose level (g/l) was 1.49 +/- 0.7, 1.48 +/- 0.7, 1.59 +/- 0.8 and 1.89 +/- 0.9 respectively. Only 0.9% of betahydroxybutyrate values were > or =0.3 mmole/l when blood glucose exceeded 2.5 g/l. Our study indicates that ketonemia self monitoring can be a valuable tool to screen insulin deficiency in patients on CSII with a low risk of false positive if we consider a threshold of 0.3 mmole/l for ketone bodies.