Decline In Beta-cell Function Research Articles

The Role of Vegan Diets in Lipotoxicity-Induced Beta-Cell Dysfunction in Type-2-Diabetes

Type-2-diabetes is considered the new plague of the current century and both, its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both were associated with obesity and pathologically elevated concentrations of circulating free fatty acids in the blood.
 The harmful effects of chronically elevated free fatty acid levels on glucose homeostasis and non-adipose tissues are referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable and both, dietary fat quantity and quality may impact beta-cell function.
 Diets high in saturated fats are especially harmful to beta-cells while (poly-)unsaturated fatty acids were associated with beta-cell protective effects. This review examined how a dietary modification towards a low-fat vegan diet, which is particularly low in saturated and trans-fats, could help to prevent or reduce lipotoxicity-induced beta cell dysfunction.
 Several potential mechanisms of action were identified including: (1) reduced total fat intake (fat quantity), (2) a more favorable polyunsaturated fatty acid to saturated fatty acid ratio (fat quality), (3) improved body weight and a reduction in adipose tissue mass, and finally (4) improved glycemic control. The latter appears of paramount importance in light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels.
 All four mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes and may reduce the likelihood of lipotoxic events to occur. Physicians must consider these findings when counseling patients on lifestyle and nutrition.

A quantitative measure of treatment response in recent-onset type 1 diabetes.

IntroductionThis paper develops a methodology and defines a measure that can be used to separate subjects that received an experimental therapy into those that benefitted from those that did not in recent‐onset type 1 diabetes. Benefit means a slowing (or arresting) the decline in beta‐cell function over time. The measure can be applied to comparing treatment arms from a clinical trial or to response at the individual level.MethodsAn analysis of covariance model was fitted to the 12‐month area under the curve C‐peptide following a 2‐hour mixed meal tolerance test from 492 individuals enrolled on five TrialNet studies of recent‐onset type 1 diabetes. Significant predictors in the model were age and C‐peptide at study entry. The observed minus the model‐based expected C‐peptide value (quantitative response, QR) is defined to reflect the effect of the therapy.ResultsA comparison of the primary hypothesis test for each study included and a t test of the QR value by treatment group were comparable. The results were also confirmed for a new TrialNet study, independent of the set of studies used to derive the model. With our proposed analytical method and using QR as the end‐point, we conducted simulation studies, to estimate statistical power in detecting a biomarker that expresses differential treatment effect. The QR in its continuous form provided the greatest statistical power when compared to several ways of defining responder/non‐responder using various QR thresholds.ConclusionsThis paper illustrates the use of the QR, as a measure of the magnitude of treatment effect at the aggregate and subject‐level. We show that the QR distribution by treatment group provides a better sense of the treatment effect than simply giving the mean estimates. Using the QR in its continuous form is shown to have higher statistical power in comparison with dichotomized categorization.

The Role of Vegan Diets in Lipotoxicity-induced Beta-cell Dysfunction in Type-2-Diabetes: A Narrative Review.

Type-2-diabetes is considered the new plague of the current century and its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both are associated with obesity and prolonged exposure to pathologically elevated concentrations of circulating free fatty acid (FFA) levels in the blood. Fatty acid derivatives may interfere with beta-cell function and ultimately lead to their death through lipoapoptosis. The harmful effects of chronically elevated FFA levels on glucose homeostasis and non-adipose tissues are generally referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable, and both dietary fat quantity and quality may impact their function. Diets high in saturated fat are especially harmful to beta-cells while (poly-)unsaturated fatty acids (PUFA) are associated with beta-cell protective effects. Therefore, this narrative review suggests that a dietary modification toward a low-fat vegan diet might help to prevent or reduce lipotoxicity-induced beta-cell dysfunction. By cutting the oversupply of saturated fat and reducing total calorie intake, and by improving both body weight and glycemic control, low-fat vegan diets may reduce the likelihood of lipotoxic events to occur. In light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels, improved glycemic parameters appear to be of utmost importance. These mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes who choose a low-fat vegan diet. Physicians must consider these findings when counseling patients on lifestyle modifications and healthy nutrition.

The impact of phenotype, ethnicity and genotype on progression of type 2 diabetes mellitus.

AimTo conduct a comprehensive review of studies of glycaemic deterioration in type 2 diabetes and identify the major factors influencing progression.MethodsWe conducted a systematic literature search with terms linked to type 2 diabetes progression. All the included studies were summarized based upon the factors associated with diabetes progression and how the diabetes progression was defined.ResultsOur search yielded 2785 articles; based on title, abstract and full‐text review, we included 61 studies in the review. We identified seven criteria for diabetes progression: ‘Initiation of insulin’, ‘Initiation of oral antidiabetic drug’, ‘treatment intensification’, ‘antidiabetic therapy failure’, ‘glycaemic deterioration’, ‘decline in beta‐cell function’ and ‘change in insulin dose’. The determinants of diabetes progression were grouped into phenotypic, ethnicity and genotypic factors. Younger age, poorer glycaemia and higher body mass index at diabetes diagnosis were the main phenotypic factors associated with rapid progression. The effect of genotypic factors on progression was assessed using polygenic risk scores (PRS); a PRS constructed from the genetic variants linked to insulin resistance was associated with rapid glycaemic deterioration. The evidence of impact of ethnicity on progression was inconclusive due to the small number of multi‐ethnic studies.ConclusionWe have identified the major determinants of diabetes progression—younger age, higher BMI, higher HbA1c and genetic insulin resistance. The impact of ethnicity is uncertain; there is a clear need for more large‐scale studies of diabetes progression in different ethnic groups.

The Role of Vitamin D and Omega-3 PUFAs in Islet Transplantation.

Recurrence of autoimmunity and allograft rejection represent major challenges that impact the success of islet transplantation. Despite the remarkable improvements achieved in immunosuppression strategies after the publication of the Edmonton protocol, long-term data of intra-hepatic islet transplantation show a gradual decline in beta-cell function. Therefore, there is a growing interest in the investigation of novel, safe and effective anti-inflammatory and immunomodulatory strategies able to promote long-term islet graft survival and notable improvements in clinical outcomes of islet transplant recipients. Vitamin D has been shown to exert anti-inflammatory and immunomodulatory effects. Pre-clinical studies investigating the use of vitamin D and its analogs (alone or in combination with immunosuppressive agents and/or other anti-inflammatory agents, such as omega-3 polyunsaturated fatty acids) showed beneficial results in terms of islet graft survival and prevention of recurrence of autoimmunity/allograft rejection in animal models of syngeneic and allogeneic islet transplantation. Moreover, epidemiologic studies demonstrated that vitamin D deficiency is highly prevalent after solid organ transplantation (e.g., heart, liver or kidney transplantation). However, studies that critically assess the prevalence of vitamin D deficiency among islet transplant recipients have yet to be conducted. In addition, prospective studies aimed to address the safety and efficacy of vitamin D supplementation as an adjuvant immunomodulatory strategy in islet transplant recipients are lacking and are therefore awaited in the future.

RSSDI consensus recommendations on insulin therapy in the management of diabetes

The Research Society for the Study of Diabetes in India (RSSDI) has regularly updated its Clinical Practice Guidelines on various aspects of diabetes. The pharmacotherapeutic management of diabetes involves a plethora of agents targeting different aetiopathogenic mechanisms administered orally or via injections as well as insulin. While most people with type 1 diabetes need complete insulin replacement therapy with multiple-daily subcutaneous injections of insulin or a continuous subcutaneous insulin infusion pump, patients with type 2 diabetes may also need insulin as and when needed, especially owing to the declining beta cell function due to the progressive nature of their diabetes. To date, various insulin regimens including basal-bolus, split-mixed, premix, and prandial therapy are available which can be individualized based on the patient profile though their prescription is often perceived as complex for management of diabetes, forming a major barrier in the acceptability of insulin. In order to provide physicians with a simple guidance on different aspects of insulin use including choosing the right insulin and regime to match the individual patient, the RSSDI for the first time has formulated this guideline on insulin therapy using simple algorithms for insulin initiation as well as titrations based on a systematic literature search of new clinical evidences on all aspects of insulin use. Insulin therapy is hereby proposed as easy to initiate and maintain, efficacious, and a safer option which when administered appropriately can almost mimic physiological insulin secretion in diabetic patients and help them achieve target glucose control and minimize complications while improving their quality of life.

Treatment of Latent Autoimmune Diabetes in Adults: What is Best?

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.

The Effect of Proton Pump Inhibitors on Glycemic Control in Patients with Type 2 Diabetes.

Background: Type 2 diabetes patients have decreased pancreatic beta cell mass with a decline in beta cell function. Gastrin has increased beta cell proliferation in vitro and in animal studies. High gastric acid levels inhibit gastrin secretion. Proton pump inhibitors (PPIs) lower gastric acid, subsequently increasing gastrin levels. This may stimulate beta cell proliferation and function, and improve glycemic control. Studies with small numbers of type 2 diabetes patients have shown a slightly lower A1C in those taking PPI versus non-PPI users. Methods: This study was a retrospective multicenter electronic data analysis using data obtained from health care facilities within Veterans Integrated Service Network (VISN) 21. Patients were included if they had established care within VISN 21 and had type 2 diabetes with an A1C > 6.5%, were started on a PPI concurrently with stable doses of metformin or sulfonylurea (SFU) monotherapy, had at least two documented A1C values, and had a medication possession ratio >80% for metformin, SFU, or a PPI. Veterans were excluded if they were using insulin, combination antihyperglycemic therapy, or oral corticosteroids. A control group not using PPI was also identified. Results: There was a statistically significant decrease in A1C within each group. However, there was no statistically significant difference between the PPI and control group in the post-A1C. Conclusion: In patients with type 2 diabetes, A1C improved in both groups, but PPI addition did not affect glycemic control. Future randomized controlled trials are needed to determine the value of PPIs as a treatment option for patients with type 2 diabetes.

Effects of liraglutide addition to multiple diabetes regimens on weight and risk of hypoglycemia for a cohort with type 2 diabetes followed in primary care clinics in Saudi Arabia

Context:Available therapies for type 2 diabetes mellitus (T2DM) do not adequately control glycemia in the long term as they do not address the issue of declining beta cell function and do not impact positively on weight or cardiovascular concerns associated with the disease.Aims:To measure changes in hemoglobin A1c, weight, and hypoglycemia after the addition of liraglutide to 3 therapeutic regimens of patients with T2DM.Settings and Design:An observational cohort study that was implemented in Al-Wazarat Health Center in Riyadh, Saudi Arabia.Methods and Materials:The study included 38 T2DM patients who were screened for initiation of liraglutide in combination with their treatment regimens; sulphonylurea, sulphonylurea with basal insulin (glargine), and multiple daily injections of insulin. The cohort was followed for 12 months, and the liraglutide was started with 0.6 mg dose that escalated to 1.2 and 1.8 mg. Glycemic level and weight were measured 3 times, whereas hypoglycemia was measured 2 times.Statistical Analysis Used:Quantitative continuous paired data were compared using a paired t-test and the nonparametric Wilcoxon signed rank test.Results:There was a statistically significant reduction of hemoglobin A1c with 1.2 mg dose (mean difference = 0.84%, P = 0.003). There were no statistically significant differences regarding the effect of liraglutide in addition to the 3 treatment regimens on patients’ weight (P = 0.08, 0.472, 0.08, respectively). Regarding hypoglycemia, liraglutide has showed minimal effect.Conclusions:Sustained effect of liraglutide on glycemic control in patients with T2DM without any major hypoglycemic episodes.

Tetraspanin 7 autoantibodies predict progressive decline of beta cell function in individuals with LADA

Aims/hypothesisThe aim of this work was to investigate whether tetraspanin 7 autoantibodies (TSPAN7A) are valuable in predicting poor beta cell function in individuals with latent autoimmune diabetes in adults (LADA).MethodsThe cross-sectional study involved participants with LADA (n = 173), type 1 diabetes (n = 158), type 2 diabetes (n = 204) and healthy control participants (n = 170). The longitudinal study involved 53 participants with LADA, with a 3-year follow-up. In both cohorts, TSPAN7A in the sera were measured by a luciferase immunoprecipitation system assay, and physical and clinical characteristics were recorded.ResultsThe prevalence of TSPAN7A in LADA, type 1 diabetes, type 2 diabetes and healthy control participants was 21.4% (37/173), 26% (41/158), 0.5% (1/204) and 1.2% (2/170), respectively. Importantly, measurement of TSPAN7A significantly increased the number of individuals with LADA found to be positive for multiple antibodies (32.4% vs 22%; p < 0.001). Further logistic regression analysis demonstrated that positivity for TSPAN7A (OR 2.87, p = 0.034), disease duration (OR 1.83, p = 0.019) and GAD antibody titre (OR 2.67, p = 0.009) were risk factors for beta cell function in LADA, while BMI (OR 0.34, p = 0.001) was a protective factor. In the prospective study in individuals with LADA, the median annual decrease in rates of fasting C-peptide and 2 h postprandial C-peptide in individuals who were positive for TSPAN7A was significantly higher when compared with the decrease in those who were negative for TSPAN7A (34.6% vs 7.9%, p = 0.043 and 33.2% vs 11%, p = 0.041, respectively).Conclusions/interpretationTSPAN7A are valid islet autoantibodies for use in East Asian populations with autoimmune diabetes and can discriminate individuals with LADA who have lower beta cell function after disease progression.

Unmet Needs in the Management of Type 2 Diabetes Mellitus Patients Starting Insulin Therapy with Basal or Premix Insulin in Routine Clinical Practice in Serbia.

IntroductionType 2 diabetes mellitus (T2DM) is a progressive disease with declining beta cell function, ultimately necessitating insulin therapy. Timely introduction of adequate insulin improves management of diabetes. The aim of this study was to evaluate the unmet needs in the management of T2DM patients recently initiated on insulin therapy in routine clinical practice in Serbia.MethodsThe NEED study was a cross-sectional, observational, multicenter, real-world study conducted in Serbia, involving 26 physicians, endocrinologists, treating individuals with T2DM from 17 secondary health care institutions. Study participants were newly initiated with insulin therapy, being treated with basal or premix insulin ± oral antidiabetics (OAD) for 6–12 months.ResultsFour hundred one individuals were included in the study between October 2016 and March 2017. The mean age of study patients was 61.8 ± 9.2 years with mean BMI 30.0 ± 5.0 kg/m2, and duration of diabetes, prior to initiation of insulin therapy, was 8.4 ± 5.9 years. A basal insulin regimen was used by 287 (71.6%) and premix insulin by 114 (28.4%) subjects. The average daily dose (39.8 ± 13.9 units premix vs. 26.3 ± 13.5 units basal), dose/kg (0.47 ± 0.15 units/kg premix vs. 0.31 ± 0.17 units/kg basal), and number of injections per day were higher in the premix compared with basal insulin regimen (p < 0.01). The percentage of T2DM participants with at least one unmet need was high (95.8%). The majority of participants had two or three unmet needs. The most common unmet needs were: HbA1c > 7.0% (79.3%), at least one documented symptomatic hypoglycemia (≤ 3.9 mmol/l) event in the previous 3 months (63.8%), and two or more doses of insulin per day (53.1%). The mean individual HbA1c target was 6.8% in the NEED study cohort, with only 16% of participants reaching it. Most participants [281 (70.1%)] experienced symptomatic hypoglycemia.ConclusionsThe NEED study showed that new insulin users of either basal or premix HM insulin have many unmet needs in the first 6–12 months of treatment. This confirms that in real-life settings novel insulins should be considered in the management of T2DM to reduce the number of symptomatic hypoglycemic events and reach a better HbA1c level.FundingSanofi, Serbia.

Temporal dynamics of serum let-7g expression mirror the decline of residual beta-cell function in longitudinal observation of children with type 1 diabetes.

In type 1 diabetes mellitus (T1DM), the introduction of insulin is typically followed by a brief remission period, with subsequent gradual decline in beta-cell function. Several studies described altered profile of circulating miRNAs (microRNAs) in T1DM patients and proposed them as biomarkers of associated pathologic processes. Serum miRNA expression profile reflects residual beta-cell function and autoimmunity in T1DM. The profiling group included patients with: GCK-MODY (N = 13), T1DM (N = 9), and 10 healthy controls. The longitudinal group included 34 patients with samples collected at diagnosis of T1DM and first, third, and fourth to eighth year since diagnosis. We reanalyzed data from the profiling group for miRNAs differentially expressed between patients with T1DM, other types of diabetes and controls. Afterward, we shortlisted miRNAs on the basis of this reanalysis and literature review and quantified their expression with quantitative polymerase chain reaction. Additionally, we measured the levels of anti-islet antibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, IA2 antibodies, and ZnT8A) and C-peptide concentrations across the four timepoints in the longitudinal group. miR-24 and let-7g serum expression differed significantly between GCK-MODY, controls, and HbA1c-matched T1DM patients; P < 0.05, false discovery rate < 0.05. Autoantibodies levels showed decreasing linear trend in repeated timepoints (all P < 0.0001). C-peptide concentration peaked during the first year after diagnosis, corresponding to remission phase, and declined in consecutive measurements. This dynamic was evidenced for let-7g expression levels (P = 0.0058). The pattern of let-7g expression change during the course of diabetes mirrors that of C-peptide levels, hinting at this microRNA's association with the residual mass of the beta cells in patients with T1DM.

Insulin Pump in Difficult to Control Type 2 Diabetes: A Single Center, Five Years' Experience.

ObjectiveDue to a progressive decline in beta-cell function, a considerable number of patients with type 2 diabetes mellitus (T2D) ultimately require multiple daily injections of large doses of insulin for glycemic control. Majority of studies have reported only short-term benefits of continuous subcutaneous insulin infusion (CSII) using an insulin pump in T2D. Our five-year follow-up data of CSII in T2D is one of the few studies showing persistent benefit in glucose control in this population.Research design and methodsWe did a chart review of patients treated with an insulin pump for five years. Inclusion criteria were: type 2 diabetes, 18–75 years of age, glycosylated hemoglobin (HbA1c) more than 6.5% (48 mmol/mol) on multiple doses of insulin (MDI > four injections per day) or more than 100 units of insulin/day, wide glycemic excursions, and intractable hypoglycemia. We identified a total of 13 patients. The primary endpoint was change in HbA1c from baseline to five years. We also reviewed the difference in weight, basal insulin requirements, hypoglycemia, and patient satisfaction questionnaire at one year. Exclusion criteria were: type 1 diabetes (T1D) and pregnancy.ResultsThe HbA1c at five years was found to be 7.72% (61 mmol/mol) compared to a baseline of 8.89% (74 mmol/mol), p-value 0.0076. We did not find any increased risk of severe hypoglycemia, weight gain, and insulin requirement.ConclusionsThe beneficial effect of insulin pump persisted for five years of follow-up, suggesting it as a valuable treatment option for difficult to treat T2D.

Identification of early biological changes in palmitate-treated isolated human islets

BackgroundLong-term exposure to elevated levels of free fatty acids (FFAs) is deleterious for beta-cell function and may contribute to development of type 2 diabetes mellitus (T2DM). Whereas mechanisms of impaired glucose-stimulated insulin secretion (GSIS) in FFA-treated beta-cells have been intensively studied, biological events preceding the secretory failure, when GSIS is accentuated, are poorly investigated. To identify these early events, we performed genome-wide analysis of gene expression in isolated human islets exposed to fatty acid palmitate for different time periods.ResultsPalmitate-treated human islets showed decline in beta-cell function starting from day two. Affymetrix Human Transcriptome Array 2.0 identified 903 differentially expressed genes (DEGs). Mapping of the genes onto pathways using KEGG pathway enrichment analysis predicted four islet biology-related pathways enriched prior but not after the decline of islet function and three pathways enriched both prior and after the decline of islet function. DEGs from these pathways were analyzed at the transcript level. The results propose that in palmitate-treated human islets, at early time points, protective events, including up-regulation of metallothioneins, tRNA synthetases and fatty acid-metabolising proteins, dominate over deleterious events, including inhibition of fatty acid detoxification enzymes, which contributes to the enhanced GSIS. After prolonged exposure of islets to palmitate, the protective events are outweighed by the deleterious events, which leads to impaired GSIS.ConclusionsThe study identifies temporal order between different cellular events, which either promote or protect from beta-cell failure. The sequence of these events should be considered when developing strategies for prevention and treatment of the disease.

Association of weight gain and fifteen adipokines with declining beta-cell function in Mexican Americans.

Obesity and adipokines are associated with development of type 2 diabetes. However, limited longitudinal studies have examined their roles on declining β-cell function over time. This report assessed three adiposity measures (BMI, percent body fat, trunk fat), insulin resistance, and fifteen adipokines in relationship to longitudinal change in β-cell function measured by disposition index (DI) from frequently-sampled-intravenous-glucose-tolerance testing. The results showed that three factors were significantly and independently associated with rate of change in DI over time: rate of change in BMI (negative), rate of change in IL-6 (negative), and baseline adiponectin (positive). The association was the strongest for changing BMI and was largely explained by changing insulin resistance; the association with changing IL-6 was also largely explained by changing insulin resistance. Baseline adiponectin remained positively associated after adjustment for changing insulin resistance, suggesting an independent effect of adiponectin to preserve or improve β-cell function. These findings provide evidence and potential mechanisms for the role of obesity in promoting β-cell dysfunction, highlighting the potential importance of mitigating obesity and its metabolic effects in preventing and treating type 2 diabetes.

Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes.

Type 2 diabetes is caused by chronic insulin resistance and progressive decline in beta-cell function. Optimal beta-cell function and mass is essential for glucose homeostasis and beta-cell impairment leads to the development of diabetes. Elevated levels of circulating fatty acids (FAs) and disturbances in lipid metabolism regulation are associated with obesity, and they are major factors influencing the increase in the incidence of type 2 diabetes. Chronic free FA (FFA) treatment induces insulin resistance and beta-cell dysfunction; therefore, reduction of elevated plasma FFA levels might be an important therapeutic target in obesity and type 2 diabetes. Lipid signals via receptors, and intracellular mechanisms are involved in FFA-induced apoptosis. In this paper, we discuss lipid actions in beta cells, including effects on metabolic pathways and stress responses, to help further understand the molecular mechanisms of lipotoxicity-induced type 2 diabetes.

High Body Adiposity Drives Glucose Intolerance and Increases Cardiovascular Risk in Normoglycemic Subjects.

The objective of this study was to assess the utility of the 2-hour oral glucose tolerance test (OGTT) value to discriminate between different cardiometabolic profiles and examine the role of body composition in predicting the associated increased risk for glucose impairment, beta-cell dysfunction, and cardiovascular disease (CVD). Subjects with normal fasting glucose completed a 2-hour OGTT and were categorized to the carbohydrate metabolism alterations (CMAs) or the control group based on a 2-hour glucose threshold of 7.8 mmol/L. Body composition, visceral adipose tissue, OGTT-based parameters, and cardiovascular risk factors (CVRFs) such as hypertension, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, and smoking status were measured. Subjects with CMAs exhibited a significantly higher 1-hour postload glucose level and a greater decline in beta-cell function and CVRF profiles. After multivariate adjustment, an excess of total body and visceral fat was associated with an increased risk of CMAs, beta-cell dysfunction, CVRFs, and lower whole-body insulin sensitivity. These data support the etiopathogenic role of body and visceral fat in the development of glucose derangements and CVRFs early on in the metabolic dysregulation process. Thus, body composition analysis and OGTT assessment performed in individuals with normal fasting glucose enable a better identification of patients at risk of developing type 2 diabetes and CVD.

The relationship between FoxO1 factor and beta cells dedifferentiation

Type 2 diabetes is a chronic metabolic disorder caused by a deficiency of beta cell function leading to varying degrees of insulin deficiency and insulin resistance. The decline of beta cell function is the central part in the development of type 2 diabetes. The dedifferentiation of pancreatic beta cells is one of the important mechanisms of islet dysfunction. In recent years, it has been shown that the decrease of the activity of the transcription factor forkhead box O1 (FoxO1) is closely related to the dedifferentiation of beta cells. The study of the specific mechanism of FoxO1 involved in the dedifferentiation of beta cells and the redifferentiation of the differentiated cells will provide new ideas for the prevention and treatment of type 2 diabetes. Key words: Forkhead transcription factors/ME; Islets of langerhans/CY/PA/ME; Review

Targeting beta-cell preservation in the management of type 2 diabetes

Type 2 diabetes (T2D) is widely considered a chronic and progressive disease without cure. As beta-cell function progressively declines over time, blood glucose rises. Current management of T2D involves incremental introduction of dietary and drug therapies to achieve normoglycaemia. However, recent studies have demonstrated remission of T2D following bariatric surgery, very low calorie diet or intensive insulin therapy, raising the possibility that the declining beta-cell function in T2D may be arrested or even reversed. The point at which such interventions are introduced in the course of T2D is key for clinical benefit. Future treatment strategies should be revised to target early beta-cell preservation and thus disease remission. This article reviews the pathogenesis of beta-cell dysfunction and evidence for the clinical benefit of preserving beta-cell function in T2D, and discusses the evidence for beta-cell preservation of current glucose-lowering therapies with particular reference to their effect when initiated at the time of diagnosis of T2D.

Decline in Beta-Cell Function among Adolescents with Type 2 Diabetes Mellitus

It is well known that beta-cell function declines over time in adults with type 2 diabetes mellitus (T2DM). The beta-cell dysfunction, initially characterized by impairment in the first phase of insulin secretion following glucose stimulation, advances to a decline in second phase insulin secretion as the disease progresses. But whether this decline in beta-cell function occurs in adolescents with T2DM is uncertain. Investigators prospectively compared beta-cell functioning over time between 39 adolescents with newly diagnosed T2DM (mean age, 15 years; body-mass index z-score, 2.4) and 32 obese adolescents without T2DM of comparable body-mass index, gender, and race (mean age, 14) during a 2-year period. Recently, researchers from Duke University School of Medicine, Durham North Carolina reported that adolescents with newly diagnosed T2DM had a 25% annual decline in beta-cell function despite receiving treatment. In this study, the results of which were first presented at the American Diabetes Association (ADA), the participants were adolescents with T2DM, more than half of whom were being treated with insulin whereas 80% were taking oral anti-diabetes medications. Beta-cell function in this study, assessed at baseline and 6, 12, and 24 months was measured by insulin secretion in response to an intravenous glucose load adjusted for insulin sensitivity (disposition index). The authors observed that adolescents with T2DM had significantly higher levels of both insulin resistance and fasting glucose at baseline compared with controls. But during the two-year study, the study subjects experienced a significant increase in fasting glucose and a 25 percent annual decline in disposition index. Understandably, both these indicators remained unchanged among the controls. JMS 2017;20(2):116