Current Diabetes Reviews - Volume 15, Issue 3, 2019

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than “classical” type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive to LADA, this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than “classical” type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis have been challenged. Despite the absence of a genetic background that is exclusive for LADA this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems to therapy and follow-up, perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

Background: In order to prevent diabetes it is important to identify common, modifiable risk factors in the population. Such knowledge is extensive for type 2 diabetes but limited for autoimmune forms of diabetes. Objective: This review aims at summarizing the limited literature on potential environmental (lifestyle) risk factors for LADA. Methods: A PubMed search identified 15 papers estimating the risk of LADA in relation to lifestyle. These were based on data from two population-based studies; one Swedish case-control study and one Norwegian cohort study. Results: Studies published to date indicate that the risk of LADA is associated with factors promoting insulin resistance and type 2 diabetes such as overweight, physical inactivity, smoking, low birth weight, sweetened beverage intake and moderate alcohol consumption (protective). Findings also indicate potential effects on autoimmunity exerted by intake of coffee (harmful) and fatty fish (protective). This supports the concept of LADA as being a hybrid form of diabetes with an etiology including factors associated with both insulin resistance and autoimmunity. Conclusion: LADA may in part be preventable through the same lifestyle modifications as type 2 diabetes including weight loss, physical activity and smoking cessation. However, current knowledge is hampered by the small number of studies and the fact that they exclusively are based on Scandinavian populations. There is a great need for additional studies exploring the role of lifestyle factors in the development of LADA.

Latent Autoimmune Diabetes in Adults (LADA), although formally classified as Type 1 Diabetes (T1D), very often (at least in Western countries) appear clinically with Type 2 Diabetes (T2D)-like features as overweight and insulin resistance. LADA patients do not need exogenous insulin at the time they are diagnosed with diabetes, but a large percentage will within a few years develop need for such treatment. The decline in beta cell function progresses much faster in LADA than in T2D, presumably because of the ongoing autoimmune assault in LADA, and therefore necessitates insulin therapy much earlier in LADA than in T2D. Despite high prevalence of LADA (about 10% of the total diabetic population in many countries), the treatment of LADA patients is far less elucidated than is the case for T1D and T2D. Finding a treatment strategy for LADA from the time of diagnosis, that can reduce the decline of beta cell function, ensure adequate metabolic control and thereby reduce the risk of diabetic complications is thus an important clinical challenge. Conclusions from the randomized treatment studies so far do not indicate an optimal treatment strategy in LADA. This review aims to give an overview of current practices for the medical treatment of LADA as well as an update on results from recent studies on the treatment of the disease.

Diabetes is a multifactorial disease, caused by a complex interplay between environmental and genetic risk factors. Genetic determinants of particularly Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D) have been studied extensively, whereas well-powered studies of Latent Autoimmune Diabetes in Adults (LADA) are lacking. So far available studies support a clear genetic overlap between LADA and T1D, however, with smaller effect sizes of the T1D-risk variants in LADA as compared to T1D. A genetic overlap between LADA and T2D is less clear. However, recent studies, including large numbers of LADA patients, provide different lines of evidence to support a genetic overlap between T2D and LADA. The genetic predisposition to LADA is yet to be explored in a study design, like a genome- wide association study, which allows for analyses of the genetic predisposition independently of prior hypothesis about potential candidate genes. This type of study may facilitate the discovery of risk variants associated with LADA independently of T1D and T2D, and is central in order to determine if LADA should be considered as an independent diabetic subtype. Extended knowledge about the genetic predisposition to LADA may also facilitate stratification of the heterogeneous group of LADA patients, which may assist the choice of treatment. This mini-review summarizes current knowledge of the genetics of LADA, and discusses the perspectives for future studies.

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

Introduction: The impairment of glucose metabolism leads to hyperglycemia and type-2 diabetes mellitus. Glucokinase enzyme is the key regulator of glucose homeostasis that catalyzes the conversion of glucose to glucose-6-phosphate in liver and pancreatic cells. In hepatocytes, GK controls the glucose uptake and glycogen synthesis. The action of liver GK is controlled by Glucokinase Regulatory Protein (GKRP) partially. In fasting conditions the GKRP binds with GK and inactivate it from carbohydrate metabolism and serve as new target for treatment of diabetes mellitus. However, the GK activators as potential antidiabetic agents but results in increased risks of hypoglycemia. Conclusion: The allosteric inhibitors of the GK-GKRP interaction are coming as alternative agents that can mitigate the risk associated with GK activators. This review discusses the recent advances and current status of potential molecules targeted to GK activators and GK-GKRP disrupters.

Introduction: Diabetes Mellitus (DM) acts as an absolute mediator of cardiovascular risk, prompting the prolonged occurrence, size and intricacy of atherosclerotic plaques via enhanced Advanced Glycation Endproducts (AGEs) formation. Moreover, hyperglycemia is associated with enhanced glyco-oxidized and oxidized Low-Density Lipoprotein (LDL) possessing greater atherogenicity and decreased the ability to regulate HMG-CoA reductase (HMG-R). Although aminoguanidine (AG) prevents the AGE-induced protein cross-linking due to its anti-glycation potential, it exerts several unusual pharmaco-toxicological effects thus restraining its desirable therapeutic effects. HMG-R inhibitors/ statins exhibit a variety of beneficial impacts in addition to the cholesterol-lowering effects. Objective: Inhibition of AGEs interaction with receptor for AGEs (RAGE) and glyco-oxidized-LDL by HMG-R inhibitors could decrease LDL uptake by LDL-receptor (LDL-R), regulate cholesterol synthesis via HMG-R, decrease oxidative and inflammatory stress to improve the diabetes-associated complications. Conclusion: Current article appraises the pathological AGE-RAGE concerns in diabetes and its associated complications, mainly focusing on the phenomenon of both circulatory AGEs and those accumulating in tissues in diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, discussing the potential protective role of HMG-R inhibitors against diabetic complications.

Background and Aims: Considering that diabetic foot ulceration is one of the major health issues globally, we aimed to evaluate the risk factors associated with foot ulcers in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 81 T2DM patients (age range: 40-80 years) registered at the Diabetes Treatment Center, Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia between April and September 2015 were included in this cross-sectional study after purposive selection and assigning of patient numbers. The selected participants were interviewed and examined, and their medical records were reviewed for sensory, vibratory, and painful neuropathies; vascular insufficiency; retinopathy; and dermatological variations. The Wagner’s classification system was employed to evaluate the stage of patients’ foot ulcers. Results: Among the study participants [mean age range: 56.4 ± 6.72 years; 53 males (65.4%)], cases of loss of protective sensation, foot deformity, amputation history, and dermatological abnormalities were notable. The Wagner gradation value of ulcers were grade 0 for 16% study population, grade 1 for 35.8%, grade 2 for 45.7%, grade 3 for 2.5%, and grades 4 and 5 for 0%. Approximately 19% of the patients had a previous case of amputation and 29.6% had nail disease. The most common footwear reported to be used by the patients was sandals shoes (46%). Conclusion: The issues of loss of protective sensation, vascular insufficiency, deformity, previous amputations, and dermatological abnormalities of the lower limbs were found to be most common among the foot ulceration patients. The study findings thus recommend regular foot examination, following basic hygiene habits, encouragement of the use of appropriate footwear, patient education about foot ulcers, and prompt treatment for minor injuries to prevent further ulceration in DM patients.

Objectives: The study aimed to explore the predictors affecting patient satisfaction to glucose monitoring system (GMSS) and drug attitude inventory (DAI) / treatment adherence among type 2 diabetes mellitus patients. Methods: Cross-sectional observational study design was used to conduct this study. Subjective assessments were made by questionnaires and objective data was collected from the patients' medication profiles registered to diabetic clinics. Patients were recruited from five different public hospitals of Hyderabad region, India. A total of 430 patients completed for analysis. The predictors to GMSS dimensions and adherence status were analyzed with Wilks's lambda effect and multivariate generalized linear model (GLM/MANOVA). Results: Study population consisted of 64.4% males and 35.6% females, age mean ± SD (43.3±11.42) years, majority of the study of participants were in between 40-60 years of age (53.3%). Majority of participants were considered healthy on BMI scale (67.2%), in contrast 234 (54.4%) reported high glycemic index with Hb1Ac (> 7.5%). Descriptive distribution pattern showed 241 (56.1%) participants were moderately satisfied with the current monitoring system. However, 157 (36.5%) reported poor satisfaction to GMSS scale score. Findings showed that low mean score of openness and worthwhileness are reported among nonadherent participants. Behavioral burden significantly high among nonadherent patients then adherents. However, emotional burden showed no effect on treatment adherence. Conclusion: This study found high rates of poor glucose monitoring system satisfaction along with low-to-poor treatment adherence among T2DM patients. Individual characteristics and clinical parameters significantly and positively predict the variance of GMSS and DAI among patients' with T2DM.

Background: Correct insulin injection practice is essential for better diabetic control. The aim of this study is to investigate the level of competency of prefilled insulin pen usage (injection technique and storage) among diabetes patients in Saudi Arabia. Methods: A cross-sectional survey between March 2017 to July 2017 of randomly selected patients with diabetes attending Diabetes Treatment Center, Prince Sultan Military Medical City, Saudi Arabia, who are actively using a prefilled insulin pen, were interviewed to complete a pre-structured questionnaire to assess the competency of using the insulin pen. The contents of the questionnaire addressed the 6 competency components according to manufacturer recommendation (priming, count time, storage, using new needles, a store with no needles, and discard date), background, clinical and metabolic data. Results of the questionnaire were analyzed to identify common pitfalls and were also contrasted with background clinical and metabolic data. Results: 165 patients with diabetes (aged 14-70yrs) were interviewed for the study and all questioners completed properly. Only 14 (8.5%) patients were following all of the six competency components. Count time 52 (31.6%) was the least followed competency component of the six, whereas discard date and storage of insulin pen were the most followed with 165 (100%) and 159 (96.4%), consecutively. Education was the only significant variable related to the following more than 3 of the competency components, and logistic regression showed the college or higher educated patients to be three times more likely follow more than 3 of the competency components. Conclusion: The study concluded that majority of patients are either ignoring or unaware of the major components of correct use of prefilled insulin in Saudi Arabia.

Background: Type 2 diabetes (T2DM) is a risk factor for Alzheimer’s disease and mild cognitive impairment. The etiology of cognitive impairment in people with T2DM is uncertain but, chronic hyperglycemia, cerebral micro vascular disease, severe hypoglycemia, and increased prevalence of macro vascular disease are implicated. Objectives: To determine the serum levels of soluble vascular adhesion molecule (sVCAM-1) and highly sensitive C-reactive protein (hs-CRP) in elderly type 2 diabetics with mild cognitive impairment (MCI). Methods: Our study was conducted on 90 elderly subjects (aged 60 years old or more). They were divided into Group Ц#134;, 30 patients with T2DM and mild cognitive impairment, group Ц#134;Ц#134;, 30 patients with T2DM without cognitive impairment and group III, 30 healthy subjects as a control group. They were subjected to history taking, full clinical examination, anthropometric measurement, the Addenbrooke’s Cognitive Examination III (ACE---III 2012), Fasting plasma glucose, 2 hours plasma glucose, HbA1c, lipid profile, protein/creatinine ratio, serum sVCAM-1 and hs-CRP. Results: Serum levels of sVCAM-1 in diabetic elderly patients with MCI were significantly higher (946.7 ± 162.01 ng/ml) than diabetic elderly patients without cognitive impairment (479.06 ± 65.27 ng/ml) and control (263.7 ± 72.05 ng/ml) with (P=0.002). Serum levels of Hs-CRP in diabetic elderly patients with MCI were significantly higher than as diabetic elderly patients without cognitive impairment and control with (P=0.005). Conclusion: Elderly diabetic patients with mild cognitive impairment have higher levels of soluble adhesion molecules and markers of low-grade systemic inflammation than other groups.