This review describes a prolonged research endeavour to test the twin cycle hypothesis that type 2 diabetes is caused by fat-induced dysfunction of the liver and pancreas, guided by the happenstance of clinical practice. Testing of the personal fat threshold hypothesis, that individuals exhibit different levels of tolerance to intra-organ fat accumulation, is also described. Both hypotheses predict that type 2 diabetes is potentially reversible by weight loss. The results of the Counterpoint study supported the twin cycle hypothesis, leading to a second study which determined that short-duration diabetes was more likely to remit following the 10-15 kg weight loss. It also confirmed that remission was durable over 6 months on an isoenergetic, normal diet. Subsequently, it was shown that weight loss caused an immediate decrease of pancreas fat only in people with type 2 diabetes and also that postprandial incretin spikes after bariatric surgery had no role in normalising fasting plasma glucose. DiRECT, a 2 year randomised controlled study, demonstrated clinical utility, observing functional beta cell capacity to return almost to normal over 12 months. A small group of participants regained weight and redeveloped type 2 diabetes, allowing observation that the underlying pathophysiological mechanisms during onset of diabetes were as postulated by the twin cycle hypothesis. Major clinical benefit was demonstrated after a further 3 year follow-up in routine care, halving the incidence of serious adverse effect compared with the standard treatment control group. In answer to the question of whether individuals have a personal fat threshold for tolerance of fat, stepwise weight loss in people with type 2 diabetes and BMI in the range 21-27 kg/m2 resulted in remission in 70%, with a wide range of fat thresholds. Type 2 diabetes can be regarded as a condition of homogenous aetiology in genetically heterogenous individuals.

Despite the recognition by key guidelines that achieving early glycaemic control has important benefits in individuals with type 2 diabetes (T2D) and that addressing excess adiposity is one of the central components of comprehensive person-centred T2D care, a substantial proportion of individuals with T2D do not meet their metabolic treatment goals. Prior treatment paradigms were limited by important treatment-associated risks such as hypoglycaemia and body weight gain. Therefore, a more conservative, sequential approach to treatment was typically utilized. One potential consequence of this approach has been a missed opportunity to achieve a 'legacy effect', where early treatment to reach glycaemic targets is associated with enduring long-term benefits in T2D. Additionally, while previous treatment approaches have addressed core defects in T2D, including insulin resistance and β-cell function decline, they have been unable to address one of the underlying causal abnormalities-excess adiposity. Here, we review currently available evidence for the beneficial long-term effects of early glycaemic control and management of body weight in people with T2D and discuss potential next steps.

The global prevalence of end-stage kidney disease (ESKD) is increasing despite optimal management of traditional risk factors such as hyperglycaemia, hypertension, and dyslipidaemia. This study examines the influence of cardiorenal risk factors, socioeconomic status, and ethnic and cardiovascular comorbidities on ESKD outcomes in the general population.

This cross-sectional study analysed data from 502,408 UK Biobank study participants recruited between 2006 and 2010. Multivariable logistic regression models were fitted to assess risk factors for ESKD, with results presented as adjusted odds ratio (aOR) and 95% confidence intervals (95% CI).

A total of 1191 (0.2%) of the study participants reported ESKD. Diabetes increased ESKD risk by 62% [1.62 (1.36-1.93)], with early-onset diabetes (before age 40) conferring higher odds compared to later-onset (after age 40) [2.26 (1.57-3.24)]. Similarly, early-onset hypertension (before age 40), compared to later onset (after age 40), increased ESKD odds by 73% [1.73 (1.21-2.44)]. Cardiovascular comorbidities, including stroke, hypertension, myocardial infarction and angina, were strongly associated with ESKD [5.97 (3.99-8.72), 5.35 (4.38-6.56), 4.94 (3.56-6.78), and 4.89 (3.47-6.81)], respectively. Males were at 22% higher risk of ESKD than females [1.22 (1.04-1.43)]. Each additional year of diabetes duration increased ESKD odds by 2% [1.02 (1.01-1.03)]. Non-white ethnicity, compared to white and socioeconomically most deprived, compared to the least deprived quintiles, were at 70% and 83% higher odds of ESKD. Each unit of HbA1c rise increased the odds of ESKD by 2%. Compared to microalbuminuria, macroalbuminuria increased the odds of ESKD by almost 10-fold [9.47 (7.95-11.27)] while normoalbuminuria reduced the odds by 73% [0.27 (0.22-0.32)].

Early onset of diabetes and hypertension, male sex, non-white ethnicity, deprivation, poor glycaemic control, and prolonged hyperglycaemia are significant risk factors for ESKD. These findings highlight the complexity of ESKD and the need for multifactorial targeted interventions in high-risk populations.

Not applicable.

Background/Objectives: Systemic and tissue inflammation play a crucial role in the pathophysiology of cardiometabolic disorders. Presepsin is a newly discovered marker of acute phase inflammation that is produced by monocytes or macrophages in response to bacterial infection and is a soluble fraction of the lipopolysaccharide (LPS) receptor. LPS is an endotoxin that, through the breakdown of the intestinal barrier, penetrates the systemic circulation and is an important bacterial mediator in the pathogenesis of sepsis and septic shock. Methods: A narrative review of the existing literature. Results: A growing body of evidence demonstrates that intestinal dysbiosis is involved in the pathogenesis of diabetes mellitus (DM) and cardiovascular (CV) disease, leading to increased circulating LPS concentrations in people with cardiometabolic disorders, even in the absence of infection. These data provide the theoretical background for a link between presepsin, DM, and CV pathology. Preliminary studies suggest that presepsin levels are downregulated in patients with well-controlled type 2 DM and correlate with continuous glucose monitoring metrics in infection-free individuals with type 1 DM. However, prospective data on the association between presepsin and the risk of diabetic complications are currently lacking. Presepsin has also been found to be elevated in infection-free individuals with myocardial infarction, heart failure, and myocarditis compared to controls and has been shown to correlate with mortality risk in subjects at high CV risk. Conclusions: The clinical utility of presepsin in the monitoring of patients with cardiometabolic disorders warrants further investigation by future studies.

Little is known about the population-based mismatch between phenotypic and genetic BMI (BMI-PGM) and its association with type 2 diabetes. We therefore used data from the China Kadoorie Biobank and UK Biobank and calculated BMI-PGM for each participant as the difference between the percentile for adjusted BMI at baseline and the percentile for adjusted polygenic risk score for BMI. Participants were categorized into discordantly low (BMI-PGM < the first quartile), concordant (the first quartile ≤ BMI-PGM < the third quartile), and discordantly high (BMI-PGM ≥ the third quartile) groups. We calculated adjusted hazard ratios (HRs) for the association of BMI-PGM and type 2 diabetes using Cox proportional hazard models in each cohort, and combined HRs using random-effects meta-analyses. During a median follow-up of 12 years for both cohorts, BMI-PGM was associated with the risk of type 2 diabetes, with the discordantly low group showing reduced risk and the discordantly high group showing elevated risk compared with the concordant group, independent of BMI and other conventional risk factors. In addition, normal-weight individuals with discordantly high BMI-PGM faced a higher risk of type 2 diabetes than overweight individuals. These findings suggest that BMI-PGM may play a potential role in reassessing the risk of type 2 diabetes, particularly among normal-weight populations.

Social developments have fostered an "obesogenic environment" that exacerbated phenotypic versus genetic mismatch of BMI (BMI-PGM) and the risk of type 2 diabetes. The study quantified BMI-PGM and examined its association with type 2 diabetes independent of BMI and other conventional factors. The risk of type 2 diabetes was lower in the discordantly low BMI-PGM group and higher in the discordantly high BMI-PGM group, with concordant BMI-PGM group as reference. These findings indicate the potential to reassess type 2 diabetes risk by quantifying BMI-PGM on individual levels.

Objective: FKBP5 is a critical gene involved in regulating the hypothalamic-pituitary-adrenal (HPA) axis and stress response. Aberrant DNA methylation at FKBP5 cytosine-phosphate-guanine (CpG) sites, such as cg22363520 and cg00862770, has been implicated in mental health disorders and metabolic diseases, including Type 2 diabetes. Exercise is a modulator of DNA methylation and metabolic health. This study investigates the interaction between exercise, diabetes, and FKBP5 methylation at cg22363520 and cg00862770 and explores their implications for mental health and disease development. Materials and Methods: FKBP5 methylation levels at cg22363520 and cg00862770 were analyzed in a cohort stratified by diabetes and exercise. Multiple linear regression models assessed the main effects and interactions of exercise and diabetes on FKBP5 methylation, with further stratified analyses for site-specific effects. Results: Exercise and diabetes showed significant and site-specific effects on FKBP5 methylation at cg22363520 and cg00862770. At cg22363520, exercise significantly reduced methylation levels in nondiabetic participants (β = -0.00195, p = 0.0157), while no significant effect was observed in diabetic individuals. Conversely, at cg00862770, exercise significantly decreased methylation levels in diabetic participants (β = -0.00611, p = 0.0081), with no significant effect in the nondiabetic group. Diabetes itself was associated with increased FKBP5 methylation at both sites, particularly in individuals without regular exercise. Additionally, significant interaction effects between exercise and diabetes were identified for both cg22363520 (p = 0.0336) and cg00862770 (p = 0.0021), highlighting the interplay between metabolic status and physical activity in regulating FKBP5 methylation. Conclusion: This study demonstrates that the effects of exercise on FKBP5 methylation are site-specific and influenced by diabetes status. Exercise reduces methylation at cg22363520 in nondiabetics and at cg00862770 in diabetics, indicating its role in modulating epigenetic regulation of stress and metabolic pathways. These findings underscore the interplay between exercise, diabetes, and FKBP5 methylation, with potential implications for improving mental health and metabolic outcomes.

The development of magnetic resonance methods for quantifying intra-organ metabolites has permitted advances in the understanding of fasting and post-prandial carbohydrate and lipid handling in people with and without type 2 diabetes. Insulin resistance in the liver was shown to be related to excess intra-organ fat and was able to be returned to normal by weight loss. The practical effect of having muscle insulin sensitivity in the lower part of the wide normal range resulted in the obligatory shunting of carbohydrates via de novo lipogenesis into saturated fat. These observations provided the basis for the Twin Cycle Hypothesis of the aetiology of type 2 diabetes. Subsequent studies on people with type 2 diabetes confirmed the postulated pathophysiological abnormalities and demonstrated their reversibility by dietary weight loss of 10-15 kg. Overall, the fundamental understanding of the mechanisms causing type 2 diabetes has bridged physiological and clinical perspectives. Large population-based randomised controlled trials confirmed the practical clinical application of the method of achieving substantial weight loss, and an NHS programme is now in place offering potential remission to people within 6 years of diagnosis.

Type 2 diabetes mellitus (T2D) has acquired epidemic proportions worldwide. In recent years, new oral glucose-lowering drugs (OGLD) have emerged that improve the cardiovascular-kidney-metabolic control in T2D people.

To compare the baseline clinical-biological characteristics among T2D people to whom had added-on dapagliflozin (DAPA group) or another OGLD (SOC group) second-line hypoglycaemic therapies among the AGORA study population.

This is a multicentre cross-sectional observational study of the baseline characteristics of T2D people recruited through competitive sampling among 46 primary care health centres in Spain for the AGORA study. The inclusion and exclusion criteria of participants, and justification of the sample size are reported. After verifying the data necessary to be evaluated and informed consent, 317 subjects were included to the DAPA group and 288 to the SOC group. Both categorical and continuous variables were analysed and compared with the usual statistics. Cohen's d was used to assess the standardised difference in means.

Six hundred and five patients with T2D were assessed (mean age 63.5 [SD±8.1] years, 61.8% men), whom 17.4% were smokers, 47.6% had obesity, 74.8% hypertension, 87.3% dyslipidaemia, and 41.7% reported physical inactivity, with no significant differences between both comparison groups. The mean (SD) evolution time of T2D was 10.1 (5.6) years. Most baseline clinical-biological characteristics at recruitment were similar in both groups. However, DAPA group was younger (2.9 years), and had lower systolic blood pressure (SBP) (2.8mmHg), higher body weight (BW) (3.7kg), and higher glycated haemoglobin A1c (HbA1c) (0.3%) than SOC group. Only 11.5% of participants had poor glycaemic control (HbA1c>8%) at recruitment, 54.9% had good glycaemic control (HbA1c<7%), being significantly lower in the DAPA group (47.3%) than in the SOC group (63.4%). The percentage of T2D patients with high vascular risk (VR) was 46.3%, and 53.7% with very high VR, being significantly higher in the DAPA group (57.4%) than in the SOC group (49.6%).

Most baseline cardiovascular-kidney-metabolic characteristics were similar in T2D patients whom had added dapagliflozin on second-line hypoglycaemic therapy as those whom had added-on another OGLD. However, patients whom had added-on dapagliflozin had higher VR, lower SBP, higher BW, and slightly worse HbA1c control. Future research is necessary to explain the causes of these differences in cardiometabolic control.

The convergence of diabetology and nanotechnology has emerged as a promising synergy with the potential to revolutionize the management and treatment of diabetes mellitus. Diabetes, a complex metabolic disorder affecting millions worldwide, necessitates innovative approaches to enhance monitoring, diagnosis, and therapeutic interventions. Nanotechnology, a burgeoning field that manipulates materials at the nanoscale, offers unprecedented opportunities to address the challenges posed by diabetes. This abstract explores the multifaceted interface between diabetology and nanotechnology, highlighting key areas of integration. Nanotechnology has paved the way for the development of advanced glucose monitoring systems with enhanced accuracy, sensitivity, and patient convenience. Miniaturized biosensors and implantable devices equipped with nanoscale materials enable continuous and real-time glucose monitoring, empowering individuals with diabetes to make timely and informed decisions about their dietary and insulin management. Furthermore, nanotechnology has facilitated breakthroughs in targeted drug delivery, addressing the limitations of conventional therapies in diabetes treatment. Nano-sized drug carriers can improve bioavailability, enable controlled release, and enhance the selectivity of therapeutic agents, minimizing side effects and optimizing treatment outcomes. Moreover, nanoengineered materials have opened avenues for tissue engineering and regenerative medicine, offering the potential to restore damaged pancreatic islets and insulin-producing cells. The amalgamation of diabetology and nanotechnology also holds promise for early disease detection and prevention. Nanoscale diagnostic tools, such as biomarker-based nanoprobes and lab-onchip devices, offer rapid and accurate detection of diabetes-related biomolecules, enabling timely interventions and reducing the risk of complications. However, this compelling combination also presents challenges that warrant careful consideration. Safety, biocompatibility, regulatory approval, and ethical implications are crucial factors that demand meticulous evaluation during the translation of nanotechnology-based solutions into clinical practice. In conclusion, the integration of diabetology and nanotechnology represents a transformative paradigm that has the potential to reshape the landscape of diabetes management. By harnessing the unique properties of nanoscale materials, researchers and clinicians are poised to usher in an era of personalized and precise diagnostics, therapeutics, and preventive strategies for diabetes mellitus. As advancements in nanotechnology continue to unfold, the journey towards realizing the full potential of this compelling combination remains an exciting frontier in medical science. This review has thoroughly and critically studied the usage of nanomedicine in the diagnosis, monitoring, and management of diabetes and its effects, providing a clear picture of their potential clinical application in the future. This evaluation covers additional numerous clinical trials research and patents that are currently in way in this subject. Thus in the light of this we intended to provide a broad picture of the state of technological development in the area of diabetes management through nanotechnology.

The incidence, prevalence, mortality, and health expenditure associated with diabetes continue to grow, despite efforts. The use of multianalyte sensors, which detect glucose as well as key analytes such as ketones, lactate, insulin, uric acid, and electrolytes, may provide additional information to guide earlier identification and management of diabetes and its complications. We undertook a narrative review using a systematic approach in May 2023, with a bridge search undertaken in April 2024. Four biomedical databases were searched: MEDLINE (Ovid), Embase, Emcare, and Cochrane Library. Searches for gray literature were conducted on ClinicalTrials.gov, Google Scholar, and websites of relevant organizations. Included studies incorporated articles on multianalyte sensors in diabetes and single-analyte sensors proposing integration into multianalyte diabetes management, with no limits placed on publication date and study design. Data were screened and extracted using CovidenceTM software. Overall, 11 articles were included, of which 7 involved multianalyte sensors (involving glucose and other analytes) and 4 single-analyte sensors (measuring non-glucose substances for proposed future integration into multianalyte systems). Analytes examined were ketones (n = 3), lactate (n = 4), uric acid (n = 3), insulin (n = 1), and potassium (n = 1). Results demonstrated that in vitro and in vivo measurements of multi- and single-analyte sensors accurately and reliably corresponded with human capillary and serum samples. While the literature on this topic is sparse, our review demonstrated that measurement of glucose and other analytes can be feasibly undertaken using multi- and single-analyte sensors. More studies in humans are needed to establish clinical utility in diabetes self-management and assist with technological improvements.

Younger-onset type 2 diabetes is associated with accelerated complications. We assessed whether complications and mortality rates differed for younger age compared with older age at diagnosis over 30 years of follow-up.

In this study, we used data from the UKPDS, collected between 1977 and 2007, of participants aged 25-65 years with newly diagnosed type 2 diabetes with younger-onset (younger than 40 years) or later-onset (40 years or older), and without diabetes autoantibodies. We analysed standardised mortality ratios (SMR) using UK general population data, and incidence rates of prespecified outcomes by 10-year age intervals at diagnosis.

Of 4550 participants testing negative to all measured autoantibodies, 429 (9·4%) had younger-onset type 2 diabetes. 2704 (59·4%) were male, and mean HbA1c was 76 mmol/mol (SD 24·6). The median follow-up was 17·5 years (IQR 12·7-20·8). SMR for younger-onset type 2 diabetes was higher (3·72 [95% CI 2·98-4·64]) compared with later-onset type 2 diabetes (1·54 [1·47-1·61]). The incidence rate was higher for all outcomes in later-onset type 2 diabetes, except for microvascular disease (younger-onset 14·5 (11·9-17·7) vs later-onset 12·1 (11·3-13·0) per 1000 person-years). However, at any given age, the 5-year incidence of any diabetes-related endpoint, all-cause mortality, microvascular disease, and myocardial infarction was higher with younger age at diagnosis. Annual mean HbA1c was higher in the first 20 years in younger-onset compared with later-onset type 2 diabetes. Among participants randomised to intensive versus conventional glycaemic control, we observed no interactions by subgroup of younger-onset versus later-onset type 2 diabetes for any outcome.

The risk of dying relative to the general population is even greater for people diagnosed with type 2 diabetes at younger ages. The increased risk of complications and poorer glycaemic control in younger-onset type 2 diabetes calls for the development of services to identify and manage these individuals.

National Institute of Health and Care Research's Biomedical Research Centre.

The application of clinical practice guidelines (CPGs) across the spectrum of individuals living with diabetes can be challenging, particularly in older adults, where factors such as frailty and multimorbidity exacerbate the complexity of management.

This systematic review aimed to explore the guidance provided within diabetes CPGs for management of individuals who are older and/or frail, including recommendations for haemoglobin A1C (HbA1c) target and pharmacotherapeutic management.

A systematic search was completed in Medline and Embase to identify national or international type 2 diabetes CPGs published in the last 10 years. Data extracted included recommendations for HbA1c targets and pharmacotherapy in older and frail adults, frailty screening and deprescribing. Quality of included CPGs was appraised with the AGREE II tool.

Twenty-three CPGs were included, within which older adults and frailty were discussed in 21 and 14 CPGs, respectively. Specific HbA1c targets for older and/or frail adults were provided by 15 CPGs, the majority of which suggested a strict target (<7.0%-7.5%) in healthier older adults and a more relaxed target (<8.0%-8.5%) in those who are frail or medically complex. Ten CPGs provided recommendations for insulin therapy and 16 provided recommendations for non-insulin antihyperglycaemic agents that were specific to older and/or frail populations, which primarily focused on minimising risk of hypoglycaemia.

Most diabetes CPGs recommend strict HbA1c targets in healthier older adults, with more relaxed targets in those living with frailty or medical complexity. However, significant variability exists in pharmacotherapy recommendations and there were proportionately less recommendations for individuals who are frail.

Obesity is a key predictor of type 2 diabetes (T2D). However, metabolic complications are not solely due to increased BMI. We hypothesized that differences between genetically predicted BMI and observed BMI (BMI-diff) could reflect deviation from individual set point and may predict incident T2D.

From the UK Biobank cohort, we selected participants of European ancestry without T2D (n = 332,154). The polygenic risk score for BMI was calculated via Bayesian regression and continuous shrinkage priors (PRS-CS). According to the BMI-diff, the 10-year risk of T2D was assessed using multivariable Cox proportional hazards model. Independent data from the Korean Genome and Epidemiology Study (KoGES) cohort from South Korea (n = 7,430) were used for replication.

Participants from the UK Biobank were divided into train (n = 268,041) and test set (n = 115,119) to establish genetically predicted BMI. In the test set, the genetically predicted BMI explained 7.1% of the variance of BMI, and there were 3,599 T2D cases (3.1%) during a 10-year follow-up. Participants in the higher quintiles of BMI-diff (more obese than genetically predicted) had significantly higher risk of T2D than those in the lowest quintile after adjusting for observed BMI: the adjusted hazard ratio of the 1st quintile (vs. 5th quintile) was 1.61 (95% CI 1.26-2.05, P < 0.001). Results were consistent among individuals in the KoGES study. Moreover, higher BMI than predicted was associated with impaired insulin sensitivity.

Having a higher BMI than genetically predicted is associated with an increased risk of T2D. These findings underscore the potential to reassess T2D risk based on individual levels of obesity using genetic thresholds for BMI.

This review paper explores post-prandial glycemia in type 2 diabetes. Post-prandial glycemia is defined as the period of blood glucose excursion from immediately after the ingestion of food or drink to 4 to 6 hours after the end of the meal. Post-prandial hyperglycemia is an independent risk factor for cardiovascular disease with glucose "excursions" being more strongly associated with markers of oxidative stress than the fasting or pre-prandial glucose level. High blood glucose is a major promoter of enhanced free radical production and is associated with the onset and progression of type 2 diabetes. Oxidative stress impairs insulin action creating a vicious cycle where repeated post-prandial glucose spikes are key drivers in the pathogenesis of the vascular complications of type 2 diabetes, both microvascular and macrovascular. Some authors suggest post-prandial hyperglycemia is the major cause of death in type 2 diabetes. Proper management of post-prandial hyperglycemia could yield up to a 35% cut in overall cardiovascular events, and a 64% cut in myocardial infarction. The benefits of managing post-prandial hyperglycemia are similar in magnitude to those seen in type 2 diabetes patients receiving secondary prevention with statins - prevention which today is regarded as fundamental by all practitioners. Given all the evidence surrounding the impact of post-prandial glycemia on overall outcome, it is imperative that any considered strategy for the management of type 2 diabetes should include optimum dietary, pharma, and lifestyle interventions that address glucose excursion. Achieving a low post-prandial glucose response is key to prevention and progression of type 2 diabetes and cardiometabolic diseases. Further, such therapeutic interventions should be sustainable and must benefit patients in the short and long term with the minimum of intrusion and side effects. This paper reviews the current literature around dietary manipulation of post-prandial hyperglycemia, including novel approaches. A great deal of further work is required to optimize and standardize the dietary management of post-prandial glycemia in type 2 diabetes, including consideration of novel approaches that show great promise.

The 20-year UK Prospective Diabetes Study showed major clinical benefits for people with newly diagnosed type 2 diabetes randomly allocated to intensive glycaemic control with sulfonylurea or insulin therapy or metformin therapy, compared with conventional glycaemic control. 10-year post-trial follow-up identified enduring and emerging glycaemic and metformin legacy treatment effects. We aimed to determine whether these effects would wane by extending follow-up for another 14 years.

5102 patients enrolled between 1977 and 1991, of whom 4209 (82·5%) participants were originally randomly allocated to receive either intensive glycaemic control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the 20-year interventional trial, 3277 surviving participants entered a 10-year post-trial monitoring period, which ran until Sept 30, 2007. Eligible participants for this study were all surviving participants at the end of the 10-year post-trial monitoring period. An extended follow-up of these participants was done by linking them to their routinely collected National Health Service (NHS) data for another 14 years. Clinical outcomes were derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendances. We examined seven prespecified aggregate clinical outcomes (ie, any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease) by the randomised glycaemic control strategy on an intention-to-treat basis using Kaplan-Meier time-to-event and log-rank analyses. This study is registered with the ISRCTN registry, number ISRCTN75451837.

Between Oct 1, 2007, and Sept 30, 2021, 1489 (97·6%) of 1525 participants could be linked to routinely collected NHS administrative data. Their mean age at baseline was 50·2 years (SD 8·0), and 41·3% were female. The mean age of those still alive as of Sept 30, 2021, was 79·9 years (SD 8·0). Individual follow-up from baseline ranged from 0 to 42 years, median 17·5 years (IQR 12·3-26·8). Overall follow-up increased by 21%, from 66 972 to 80 724 person-years. For up to 24 years after trial end, the glycaemic and metformin legacy effects showed no sign of waning. Early intensive glycaemic control with sulfonylurea or insulin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 10% (95% CI 2-17; p=0·015) for death from any cause, 17% (6-26; p=0·002) for myocardial infarction, and 26% (14-36; p<0·0001) for microvascular disease. Corresponding absolute risk reductions were 2·7%, 3·3%, and 3·5%, respectively. Early intensive glycaemic control with metformin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 20% (95% CI 5-32; p=0·010) for death from any cause and 31% (12-46; p=0·003) for myocardial infarction. Corresponding absolute risk reductions were 4·9% and 6·2%, respectively. No significant risk reductions during or after the trial for stroke or peripheral vascular disease were observed for both intensive glycaemic control groups, and no significant risk reduction for microvascular disease was observed for metformin therapy.

Early intensive glycaemic control with sulfonylurea or insulin, or with metformin, compared with conventional glycaemic control, appears to confer a near-lifelong reduced risk of death and myocardial infarction. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible.

University of Oxford Nuffield Department of Population Health Pump Priming.

Chronic elevation of blood glucose at first causes relatively minor changes to the neural and vascular components of the retina. As the duration of hyperglycemia persists, the nature and extent of damage increases and becomes readily detectable. While this second, overt manifestation of diabetic retinopathy (DR) has been studied extensively, what prevents maximal damage from the very start of hyperglycemia remains largely unexplored. Recent studies indicate that diabetes (DM) engages mitochondria-based defense during the retinopathy-resistant phase, and thereby enables the retina to remain healthy in the face of hyperglycemia. Such resilience is transient, and its deterioration results in progressive accumulation of retinal damage. The concepts that co-emerge with these discoveries set the stage for novel intellectual and therapeutic opportunities within the DR field. Identification of biomarkers and mediators of protection from DM-mediated damage will enable development of resilience-based therapies that will indefinitely delay the onset of DR.

Metformin has been used in the management of diabetes for decades. It is an effective, low-cost intervention with a well-established safety profile. Emerging evidence suggests that metformin targets a number of pathways that lead to chronic kidney damage, and long-term use may, therefore, slow the rate of kidney function decline and chronic kidney disease (CKD) progression.

To evaluate the effect of metformin therapy on kidney function decline in patients with CKD with or without diabetes mellitus and assess the safety and dose tolerability in this population.

We searched the Cochrane Kidney and Transplant Register of Studies up to 19 July 2023 with assistance from an Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

We included randomised controlled trials (RCTs) that reported kidney-related outcomes with a minimum duration of 12 months delivery of the metformin intervention and whose eligibility criteria included adult participants with either i) a diagnosis of CKD of any aetiology and/or ii) those with a diagnosis of diabetes mellitus. Comparisons included placebo, no intervention, non-pharmacological interventions, other antidiabetic medications or any other active control. Studies that included patients on any modality of kidney replacement therapy were excluded.

Two authors independently carried out data extraction using a standard data extraction form. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

This review included 11 studies reporting on 8449 randomised participants. Studies were conducted in patient populations with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (four studies) or diabetes mellitus (seven studies). Six studies compared metformin with no active control, four studies compared metformin with active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), and one study included treatment arms that randomised to either metformin, diet and lifestyle modifications, or other antidiabetic therapies. The risk of bias in included studies varied; two studies were abstract-only publications and were judged to have a high risk of bias in most domains. Other included publications were judged to have a low risk of bias in most domains. Across comparisons, GRADE evaluations for most outcomes were judged as low or very low certainty, except for those relating to side effects, tolerance, and withdrawals, which were judged as moderate certainty. The evidence suggests that compared to placebo, metformin may result in i) a slightly smaller decline in kidney function (3 studies, 505 participants: MD 1.92 mL/min, 95% CI 0.33 to 3.51; I2 = 0%; low certainty), ii) very uncertain effects on the incidence of kidney failure (1 study, 753 participants: RR 1.20, 95% CI 0.17 to 8.49), iii) little or no effect on death (3 studies, 865 participants: RR 1.00, 95% CI 0.76 to 1.32; I2 = 0%; moderate certainty), iv) little or no effect on the incidence of serious adverse events (3 studies, 576 participants: RR 1.15, 95% CI 0.76 to 1.72; I2 = 0%; moderate certainty), and v) likely higher incidence of intolerance leading to study withdrawal than placebo (4 studies, 646 participants: RR 2.19, 95% CI 1.46 to 3.27; I2 = 0%; moderate certainty). The certainty of the evidence for proteinuria was very uncertain. Compared to other active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), metformin i) demonstrated very uncertain effects on kidney function decline, ii) may result in little or no difference in death (3 studies, 5608 participants: RR 0.95 95% CI 0.63 to 1.43; I2 = 0%; low certainty), iii) probably results in little or no difference in intolerance leading to study withdrawal (3 studies, 5593 participants: RR 0.92, 95% CI, 0.79 to 1.08; I2 = 0%; moderate certainty), iv) probably results in little or no difference in the incidence of serious adverse events (2 studies, 5545 participants: RR 1.16, 95% CI 0.79 to 1.71; I2 = 0%; moderate certainty), and v) may increase the urinary albumin-creatinine ratio (2 studies, 3836 participants: MD 14.61, 95% CI 8.17 to 21.05; I2 = 0%; low certainty). No studies reported the incidence of kidney failure.

This review highlights the lack of RCTs reporting on the effects of metformin on kidney function, particularly in patients with CKD. Future research in this field requires adequately powered RCTs comparing metformin to placebo or standard care in those with CKD. Seven ongoing studies were identified in this review, and future updates, including their findings, may further inform the results of this review.

The use of natural and herbal products as alternative therapies, in conjunction with blood glucose-lowering medications, is on the rise for patients with diabetes. Our objective was to conduct a systematic review and comprehensive meta-analysis of both human and animal models to investigate the impact of chamomile consumption on glycemic control.

A systematic search was conducted on all published papers from January 1990 up to January 2022 via Scopus, PubMed/Medline, Google Scholar, and ISI Web of Science. Human and animal articles evaluating the effect of chamomile on serum glycemic markers were included. We used the random-effects model to establish the pooled effect size. The dose-dependent effect was also assessed.

Overall, 4 clinical trials on human and 8 studies on animals met the inclusion criteria. With regard to RCTs, a favorable effect of chamomile consumption on serum fasting blood glucose (Standardized Mean Differences (SMD): -0.65, 95% CI: -1.00, -0.29, P < 0.001; I2 = 0%) and hemoglobin A1C (HbA1C) levels (SMD: -0.90, 95% CI: -1.39, -0.40, P < 0.001; I2 = 45.4%) was observed. Considering animal studies, consumption of chamomile extracts significantly reduced serum blood glucose (SMD: -4.37, 95% CI: -5.76, -2.98, P < 0.001; I2 = 61.2%). Moreover, each 100 mg/d increase in chamomile extract intervention resulted in a significantly declined blood glucose concentrations (MD: -54.35; 95% CI: -79.77, -28.93, P < 0.001; I2 = 94.8).

The current meta-analysis revealed that chamomile consumption could exert favorable effects on serum blood glucose and HbA1C. However, additional randomized controlled trials are needed to further confirm these findings.

The online version contains supplementary material available at 10.1007/s40200-023-01345-8.

A significant proportion of diabetic kidney disease (DKD) experience a rapid decline in eGFR, leading to end-stage kidney disease (ESKD) within months. This single-centered retrospective cohort study aimed to assess the prevalence, clinical profile, and predictors for rapid progression in type 2 diabetes mellitus (T2DM) patients with DKD.

Three hundred fifty-nine T2DM patients with DKD between January 2018 and 2022 were included and those with superimposed non-diabetic kidney disease, chronic kidney disease 5, and < 6 months follow-up were excluded. They were classified as rapid and non-rapid progressors based on the annual eGFR decline of > 5 ml/min/1.73 m2/year. The primary outcome analyzed was the progression to ESKD. The secondary outcomes were the onset of microvascular and macrovascular complications and predictors for rapid progression as well as ESKD.

In a median follow-up of 3.5 years, 61.3% were rapid progressors (mean eGFR decline of 15.4 ml/1.73m2/year) and 38.7% were non-rapid progressors (mean eGFR decline 1.8 ml/1.73m2/year. Among rapid progressors, 61.4% reached ESKD. Severe proteinuria, the presence of retinopathy, and acute kidney injury (AKI) episodes were strong predictors of rapid progression. Cardiovascular disease and diabetic retinopathy (microvascular complications) were significantly higher among rapid progressors and had a mortality rate of 7.2%.

The majority of type 2 DKD patients were rapid progressors and two-thirds of them developed ESKD. The prevalence of hypertension, cardiovascular disease, diabetic retinopathy, AKI episodes, and mortality was higher in rapid progressors. Severe proteinuria and diabetic retinopathy were found to be strong predictors for rapid eGFR decline and its progression to ESKD.

The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open?

Type 1 diabetes (T1D) is a specific autoimmune disease related to genetic and autoimmune factors. Recent studies have found that the intestinal flora is one of the important environmental factors in the development of T1D. The gut microbiota is the largest microbiota in the human body and has a significant impact on material and energy metabolism. Related studies have found that the intestinal floras of T1D patients are unbalanced. Compared with normal patients, the abundance of beneficial bacteria is reduced, and various pathogenic bacteria are significantly increased, affecting the occurrence and development of diabetes. Medicinal and food homologous traditional Chinese medicine (TCM) has a multicomponent, multitarget, and biphasic regulatory effect. Its chemical composition can increase the abundance of beneficial bacteria, improve the diversity of the intestinal flora, reduce blood sugar, and achieve the purpose of preventing and treating T1D by regulating the intestinal flora and its metabolites. Therefore, based on a review of T1D, intestinal flora, and TCM derived from medicine and food, this review describes the relationship between T1D and the intestinal flora, as well as the research progress of TCM interventions for T1D through regulation of the intestinal flora. Medicine and food homologous TCM has certain advantages in treating diabetes and regulating the intestinal flora. It can be seen that there is still great research space and broad development prospects for the treatment of diabetes by regulating the intestinal flora with drug and food homologous TCM.

The prevalence of type 2 diabetes is increasing worldwide. The aim of our study was to detect people susceptible to DM among a university population aged 18 to 45 years and analyze the existence of modifiable risk factors in order to implement prevention programs, in addition to analyzing BMI data related to the variables under study. We proposed a descriptive, cross-sectional study following the recommendations of cross-sectional studies (STROBE), with a sample of 341 subjects, students enrolled at the University of Extremadura, carried out by two researchers. The research protocol was approved by the Bioethics Committee of the University of Extremadura (165/2021). The study considered the Findrisk questionnaire in Spanish, validated by the Blackboard Study, a stadiometer to measure height, a bioimpedance meter to evaluate weight and body composition parameters, and a blood pressure monitor to measure blood pressure. The results indicated that the participants had a low risk of suffering T2DM. The highest Findrisk test scores were found in those with a BMI value above 25, lower physical activity, poor dietary intake of fruits and vegetables, and increased fat mass. Our future research will be the implementation of T2DM prevention programs, acting on modifiable factors.

Analysis of general practice records can address the information gap on the epidemiology of type 2 diabetes (T2DM) in Ireland, informing practice and the development of interventions in primary care. The aim of this study was to identify patients with poor glycaemic control, risk factors for complications and evidence of end organ damage in a large multi-practice study and to profile their characteristics.

Patients with T2DM were identified using disease coding in Health One practice management software in 41 general practices. Patients' demographics and clinical data were extracted. Rates of poor glycaemic control (glycated haemoglobin > 58 mmol/mol) and albumin creatinine ratio > 3 mg/mmol were calculated. A multilevel logistic regression analysis using both patient and practice variables was conducted.

Data was collected from 3188 patients of whom 29% (95% CI 28 to 31%) had poor glycaemic control, which was associated with younger age, higher BMI and higher total cholesterol. Only 42% of patients (n = 1332) had albumin creatinine ratio measured with 42% (95% CI 40 to 45%) of these having values > 3 mg/mmol. Older age groups, men, those with hypertension, eGFR < 60 ml/min/1.73m2 and poor glycaemic control were most associated with higher values of albumin creatinine ratio.

Analysing this large multi-practice dataset gives important information on the prevalence and characteristics of diabetic patients who are most at risk of poor outcomes. It highlights that recording of some data could be improved.

Diabetes is now one of the major public health challenges, globally. Prolonged diabetes leads to various diabetic microvascular complications (DMCs) like retinopathy, nephropathy, and neuropathy. Multiple factors are likely to be involved in predisposing diabetic individuals to complications. Early detection or diagnosis is essential in developing strategies to reduce the risk factors and management costs of these diabetic complications. In this study, we employed Raman Spectroscopy (RS) to analyse the plasma samples of diabetes patients without and with DMCs along with the plasma samples of healthy subjects. Spectral comparisons revealed decrease in protein content in Diabetes group and further subsequent decrease in proteins in DMC groups when compared with control group, which corroborates with the fact that there exists increased secretion of proteins in urine and corresponding decreased protein content in their blood in case of diabetic individuals. Among all study groups, it was noted that 75% of control spectra show correct classification, while spectral misclassification is high amongst the subjects with Diabetes and DMCs. Interestingly, very few Diabetes and DMC plasma spectra are misclassified as control spectra. Findings demonstrate that 70% of the Diabetes subjects without complications can be correctly identified from diabetes with complications. Further, investigations could also attempt to explore the use of serum instead of plasma to reduce the spectral misclassifications as one of the abundant constituents namely clotting factors could be avoided. The outcome of RS study may be imminent for the early detection or diagnosis of DMCs.

Post-pancreatitis diabetes mellitus (PPDM) is a frequent complication of pancreatitis and is associated with an increased risk of adverse outcomes. Metformin is recommended for the treatment of PPDM, but evidence of its risk-benefit profile is limited. In a pharmaco-epidemiologic study, we investigated the association between metformin treatment and adverse outcomes in patients with PPDM.

In a Danish nationwide population-based cohort study, we included adults (≥18 years) with incident PPDM or type 2 diabetes between 2009 and 2018. Post-pancreatitis diabetes mellitus was categorised into acute and chronic subtypes (PPDM-A and PPDM-C). Associations between metformin treatment and severe hypoglycaemia, major adverse cardiovascular events (MACE), and all-cause mortality were examined across the diabetes subgroups using Cox regression analysis. Treatments with metformin, insulin, and other glucose-lowering therapies were handled as time-varying exposures.

We included 222 337 individuals with new-onset type 2 diabetes and 3781 with PPDM, of whom 2305 (61%) were classified as PPDM-A and 1476 (39%) as PPDM-C. Treatment with metformin was associated with a lower risk of severe hypoglycaemia (adjusted hazard ratio [HR] 0.41, 95% CI 0.27-0.62, P < .0001), MACE (HR 0.74, 95% CI 0.60-0.92, P = .0071), and all-cause mortality (HR 0.56, 95% CI 0.49-0.64, P < .0001) in patients with PPDM. In sensitivity analyses and among individuals with type 2 diabetes, metformin treatment exhibited comparable trends of risk reduction.

Metformin is associated with a lower risk of adverse outcomes, including all-cause mortality in patients with PPDM, supporting the use of metformin as a glucose-lowering therapy for these patients.

To highlight the added benefits of approved and upcoming, centrally-acting, anti-obesity drugs, focusing not only on the most common metabolic and cardiovascular effects but also on their less explored clinical benefits and drawbacks, in order to provide clinicians with a tool for more comprehensive, pharmacological management of obesity.

Obesity is increasingly prevalent worldwide and has become a challenge for healthcare systems and societies. Reduced life expectancy and cardiometabolic complications are some of the consequences of this complex disease. Recent insights into the pathophysiology of obesity have led to the development of several promising pharmacologic targets, so that even more effective drugs are on the horizon. The perspective of having a wider range of treatments increases the chance to personalize therapy. This primarily has the potential to take advantage of the long-term use of anti-obesity medication for safe, effective and sustainable weight loss, and to concomitantly address obesity complications/comorbidities when already established. The evolving scenario of the availability of anti-obesity drugs and the increasing knowledge of their added effects on obesity complications will allow clinicians to move into a new era of precision medicine.

Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Concurrent blood pressure control has been advocated for this purpose, but individual studies have reported varying conclusions regarding the effects of this intervention.

To summarize the existing evidence regarding the effect of interventions to control blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs.

We searched several electronic databases, including CENTRAL, and trial registries. We last searched the electronic databases on 3 September 2021. We also reviewed the reference lists of review articles and trial reports selected for inclusion.

We included randomized controlled trials (RCTs) in which either type 1 or type 2 diabetic participants, with or without hypertension, were assigned randomly to more intense versus less intense blood pressure control; to blood pressure control versus usual care or no intervention on blood pressure (placebo); or to one class of antihypertensive medication versus another or placebo.

Pairs of review authors independently reviewed the titles and abstracts of records identified by the electronic and manual searches and the full-text reports of any records identified as potentially relevant. The included trials were independently assessed for risk of bias with respect to outcomes reported in this review.

We included 29 RCTs conducted in North America, Europe, Australia, Asia, Africa, and the Middle East that had enrolled a total of 4620 type 1 and 22,565 type 2 diabetic participants (sample sizes from 16 to 4477 participants). In all 7 RCTs for normotensive type 1 diabetic participants, 8 of 12 RCTs with normotensive type 2 diabetic participants, and 5 of 10 RCTs with hypertensive type 2 diabetic participants, one group was assigned to one or more antihypertensive agents and the control group to placebo. In the remaining 4 RCTs for normotensive participants with type 2 diabetes and 5 RCTs for hypertensive type 2 diabetic participants, methods of intense blood pressure control were compared to usual care. Eight trials were sponsored entirely and 10 trials partially by pharmaceutical companies; nine studies received support from other sources; and two studies did not report funding source. Study designs, populations, interventions, lengths of follow-up (range less than one year to nine years), and blood pressure targets varied among the included trials. For primary review outcomes after five years of treatment and follow-up, one of the seven trials for type 1 diabetics reported incidence of retinopathy and one trial reported progression of retinopathy; one trial reported a combined outcome of incidence and progression (as defined by study authors). Among normotensive type 2 diabetics, four of 12 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; two trials reported combined incidence and progression. Among hypertensive type 2 diabetics, six of the 10 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; five of the 10 trials reported combined incidence and progression. The evidence supports an overall benefit of more intensive blood pressure intervention for five-year incidence of diabetic retinopathy (11 studies; 4940 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.73 to 0.92; I2 = 15%; moderate certainty evidence) and the combined outcome of incidence and progression (8 studies; 6212 participants; RR 0.78, 95% CI 0.68 to 0.89; I2 = 42%; low certainty evidence). The available evidence did not support a benefit regarding five-year progression of diabetic retinopathy (5 studies; 5144 participants; RR 0.94, 95% CI 0.78 to 1.12; I2 = 57%; moderate certainty evidence), incidence of proliferative diabetic retinopathy, clinically significant macular edema, or vitreous hemorrhage (9 studies; 8237 participants; RR 0.92, 95% CI 0.82 to 1.04; I2 = 31%; low certainty evidence), or loss of 3 or more lines on a visual acuity chart with a logMAR scale (2 studies; 2326 participants; RR 1.15, 95% CI 0.63 to 2.08; I2 = 90%; very low certainty evidence). Hypertensive type 2 diabetic participants realized more benefit from intense blood pressure control for three of the four outcomes concerning incidence and progression of diabetic retinopathy. The adverse event reported most often (13 of 29 trials) was death, yielding an estimated RR 0.87 (95% CI 0.76 to 1.00; 13 studies; 13,979 participants; I2 = 0%; moderate certainty evidence). Hypotension was reported in two trials, with an RR of 2.04 (95% CI 1.63 to 2.55; 2 studies; 3323 participants; I2 = 37%; low certainty evidence), indicating an excess of hypotensive events among participants assigned to more intervention on blood pressure.

Hypertension is a well-known risk factor for several chronic conditions for which lowering blood pressure has proven to be beneficial. The available evidence supports a modest beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to five years, particularly for hypertensive type 2 diabetics. However, there was a paucity of evidence to support such intervention to slow progression of diabetic retinopathy or to affect other outcomes considered in this review among normotensive diabetics. This weakens any conclusion regarding an overall benefit of intervening on blood pressure in diabetic patients without hypertension for the sole purpose of preventing diabetic retinopathy or avoiding the need for treatment for advanced stages of diabetic retinopathy.

There is a knowledge gap of health utility values for Type 2 Diabetes Mellitus (T2DM) complications in Malaysia. This study aimed to estimate EQ-5D-5L utility values and evaluate health-related quality of life (HRQoL) for Malaysian T2DM associated with complications and clinical characteristics.

A cross-sectional study was conducted on T2DM patients at a tertiary hospital outpatient using the Malay and English version of the EQ-5D-5L questionnaire. Health utility values were derived using the Malaysian EQ-5D-5L value set. Ordinary least squares (OLS) multivariable regression model was used to estimate the health utility decrements associated with T2DM-related complications and clinical characteristics.

A total of 513 T2DM patients were recruited. Overall, pain was the most affected of all five EQ-5D-5L dimensions. Patients with foot ulcer, amputation, severe heart failure and frequent hypoglycemia reported more problems collectively in all EQ-5D-5L dimensions. Older age, lower education level, longer duration of T2DM, urine protein creatine index (UPCI) > 0.02 g/mmol, and injection therapy were significantly associated with lower EQ-5D-5L utility values (p < 0.004, Bonferroni adjusted). The lowest unadjusted utility values were reported for severe heart failure 0.65 (interquartile range, IQR 0.50), frequent hypoglycemia 0.74 (0.22) and being amputated 0.78 (0.47). In the multivariable regression model after controlling for sociodemographic and clinical characteristics, the largest utility value decrement was observed for amputation (- 0.158, SE 0.087, p = 0.05), frequent hypoglycemia (- 0.101, SE 0.030, p = 0.001), myocardial infarction (-0.050, SE 0.022, p = 0.022) and obesity (-0.034, SE 0.016, p = 0.029).

Larger utility value decrements were found for severe stages of complications. These findings suggest the value of defining severity of complications in utility elicitation studies. The utility decrement quantified for different T2DM complication severity will be useful for economic evaluations within diabetic-related fields.

Diabetic retinopathy is regarded as a common manifestation of diabetes mellitus, being a prominent cause of visual impairment and blindness. This microvascular complication is marked by the appearance of microaneurysms, elevated vascular permeability, capillary blockage, and proliferation of neovasculature. The etiology behind retinopathy is ambiguous and the efficacy of current treatment strategies is minimal. Early diagnosis of this complication using a biomarker with high sensitivity and specificity is very essential for providing better therapeutic strategies. The current available therapeutic options are limited with various adverse effects. Laser treatment is not beneficial in all the situations, economic constraints being the major challenge. Surgical interventions are employed when pharmacotherapy and laser treatment fail. New pharmacological treatments are becoming a necessity for treating the condition. This review highlights the use of various diagnostic tools, emerging biomarkers for early detection of diabetic retinopathy, pathological mechanisms associated with the disease, current therapeutic approaches used and future strategies for more enhanced treatment options and more potent pharmacological actions.

To examine sex differences in the characteristics and outcomes in participants with type 2 diabetes (T2D), with or without cardiovascular disease (CVD), randomized to once-weekly exenatide (EQW) or placebo in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

Baseline characteristics were summarized and compared by sex. Cox proportional hazards regression models were used for clinical outcomes, including the primary composite outcome of cardiovascular (CV) death, non-fatal myocardial infarction or non-fatal stroke (MACE3). Models including sex-by-treatment interaction were used to evaluate differences in effects of EQW.

Overall, 5603 women and 9149 men were followed for a median of 3.2 years. Women were younger (mean 61.4 vs. 62.2 years, P < .001) and had a shorter duration of diabetes (mean 12.9 vs. 13.2 years, P = .039) and less coronary artery disease (35.2% vs. 61.0%, P < .001) than men, but also a less favourable metabolic risk profile and lower use of cardioprotective medications. MACE3 occurred in 9.1% of women and 13.5% of men, corresponding to 2.82 versus 4.40 events/100 participant-years (adjusted hazard ratio 0.80, 95% CI: 0.70-0.93, P = .003). There was no difference in MACE3 with EQW compared with placebo, or evidence of heterogeneity of treatment effect by sex.

This analysis of a large population of individuals with T2D, with or without established CVD, identified between-sex differences in clinical characteristics and care. Despite having worse management of CV risk factors, women had significantly lower rates of important CV events not attributable to the effects of study treatment.

The aim of study is to re-evaluate the risk-benefits of intensive glycemic control in the context of multi-factorial intervention in adults with T2D.

We searched Ovid MEDLINE, Embase, Cochrane, and CINHAL for randomized control trials comparing standard glucose targets to intensive glucose targets with pre-specified HbA_1clevels. Subgroup analysis was also performed to account for the inclusion of glucose only versus multi-factorial intervention trials. Results are reported as risk ratio (RR) and 95% confidence interval (CI).

Fifty-seven publications including 19 trials were included. Compared to conventional glycemic control, intensive glycemic control decreased the risk of non-fatal myocardial infarction (0.8, 0.7-0.91), macroalbuminuria (0.72, 0.5--0.87), microalbuminuria (0.67, 0.52-0.85), major amputation (0.6, 0.38-0.96), retinopathy (0.75 ,0.63-0.9), and nephropathy (0.78, 0.63-0.97). The risk of hypoglycemia increased with intensive glycemic control than conventional treatment (2.04, 1.34-3.1). No reduction in all-cause or cardiovascular mortality was observed. However, in the context of multifactorial intervention, intensive glucose control was associated with a significant reduction in all-cause mortality (0.74, 0.57-0.95).

Targeting HbA_1c levels should be individualized based on the clinical status, balancing risks and benefits and potential risk for developing these complications among people with T2D.

Diabetes mellitus is one of the major non-communicable diseases accounting for millions of death annually and increasing economic burden. Hyperglycemic condition in diabetes creates oxidative stress that plays a pivotal role in developing diabetes complications affecting multiple organs such as the heart, liver, kidney, retina, and brain. Green tea from the plant Camellia sinensis is a common beverage popular in many countries for its health benefits. Green tea extract (GTE) is rich in many biologically active compounds, e.g., epigallocatechin-3-O-gallate (EGCG), which acts as a potent antioxidant. Recently, several lines of evidence have shown the promising results of GTE and EGCG for diabetes management. Here, we have critically reviewed the effects of GTE and EGCC on diabetes in animal models and clinical studies. The concerns and challenges regarding the clinical use of GTE and EGCG against diabetes are also briefly discussed. Numerous beneficial effects of green tea and its catechins, particularly EGCG, make this natural product an attractive pharmacological agent that can be further developed to treat diabetes and its complications.

Microvascular changes in eye and kidney shares some common factors in diabetes mellitus (DM). The purpose was to evaluate choroidal thickness (CT) and choriocapillaris (CC) density in patients with type 2 diabetes (T2D) and their association with diabetic kidney disease (DKD) using swept-source optical coherence tomography (SS-OCT).

A cross-sectional study was conducted with patients with T2D with mild or no diabetic retinopathy (DR) and non-diabetic controls. CT was measured with SS-OCT, and CC vascular density was measured with OCT angiography. These parameters were compared with inner retinal layers thickness in patients with and without DKD and non-diabetic controls.

Ninety-three eyes from patients with T2D and 34 eyes from controls volunteers were included. Within the T2D group, 56 eyes with DKD and 37 eyes from patients with no diabetic kidney disease were examined. A statistically significant reduction of CT was observed in patients with DKD compared with controls, with no difference in CC density. There was an association between ganglion cell layer and central choroidal thickness reduction in the DKD group.

Patients with T2D with DKD showed a decrease in CT with no difference in CC density compared with non-diabetic controls. This thinning might be related to vascular changes of choroidal layers such as Haller's and Sattler's with preservation of CC density, which is crucial for outer retina and retinal pigment epithelium health. Longitudinal studies are warranted to determine the association of choroidal changes with the pathogenesis of diabetes, and its association with early DKD and progression to more severe DR.

Diabetic foot ulcer (DFU) is a common diabetes mellitus (DM) complication. Individuals with DM and a DFU achieved significantly lower scores in cognitive tests than those without a DFU. We investigated whether baseline cognitive function in individuals with a DFU is a determinant of mortality.

A prospective study using data collected during a case-control study conducted in 2010-2012 whereby 90 participants with a DFU (mean age at baseline 58.28 ± 6.95 years, 75.6% male) took the paper and pencil and the NeuroTrax battery of cognitive tests. Depression was assessed, and the DFU status was evaluated. In 2020, information pertaining to participants' vital status (dead/alive) was collected and the relationship between baseline cognitive status and vital status was assessed.

During a median follow-up of 6.8 years (range 0.2-9.5), 39 participants died (43.3%). Individuals alive vs. those who had died during follow-up had a higher global cognitive score at baseline (92.16 ± 10.95 vs. 87.18 ± 12.24, p = 0.045), but increased risk was not found. Individuals who were alive vs. those who had died during follow-up had statistically significantly higher baseline executive function, reaction time and digit symbol substitution test results. However, after adjustment for glycosylated hemoglobin (HbA1c), microvascular and macrovascular complications, no relationship between cognitive tests and mortality remained significant.

The higher mortality rate among people with type 2 DM and a DFU was not significant after adjustment for HbA1c, micro- and macrovascular complications. There may be common pathophysiological pathways to both DM complications and cognitive impairment, which may contribute to increased mortality. Further studies are warranted.

In the diabetic kidneys, morbidities such as accelerated ageing, hypertension and hyperglycaemia create a pro-inflammatory microenvironment characterised by extensive fibrogenesis. Radiological techniques are not yet optimised generating inconsistent and non-reproducible data. The gold standard procedure to assess renal fibrosis is kidney biopsy, followed by histopathological assessment. However, this method is risky, invasive, subjective and examines less than 0.01% of kidney tissue resulting in diagnostic errors. As such, less than 10% of patients undergo kidney biopsy, limiting the accuracy of the current diabetic kidney disease (DKD) staging method. Standard treatments suppress the renin-angiotensin system to control hypertension and use of pharmaceuticals aimed at controlling diabetes have shown promise but can cause hypoglycaemia, diuresis and malnutrition as a result of low caloric intake. New approaches to both diagnosis and treatment are required. Nanoparticles (NPs) are an attractive candidate for managing DKD due to their ability to act as theranostic tools that can carry drugs and enhance image contrast. NP-based point-of-care systems can provide physiological information previously considered unattainable and provide control over the rate and location of drug release. Here we discuss the use of nanotechnology in renal disease, its application to both the treatment and diagnosis of DKD. Finally, we propose a new method of NP-based DKD classification that overcomes the current systems limitations.

The UK Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM) developed using 30-year (1977-2007) data from the UKPDS is widely used for health outcomes' projections and economic evaluations of therapies for patients with type 2 diabetes (T2D). Nevertheless, its reliability for contemporary UK T2D populations is unclear. We assessed the performance of version 2 of the model (UKPDS-OM2) using data from A Study of Cardiovascular Events in Diabetes (ASCEND), which followed participants with diabetes in the UK between 2005 and 2017.

The UKPDS-OM2 was used to predict the occurrence of myocardial infarction (MI), other ischemic heart disease, stroke, cardiovascular (CV) death, and other death among the 14 569 participants with T2D in ASCEND, all without previous CV disease at study entry. Calibration (comparison of predicted and observed year-on-year cumulative incidence over 10 years) and discrimination (c-statistics) of the model were assessed for each endpoint. The percentage error in event rates at year 7 (mean duration of follow up) was used to quantify model bias.

The UKPDS-OM2 substantially overpredicted MI, stroke, CV death, and other death over the 10-year follow-up period (by 149%, 42%, 269%, and 52%, respectively, at year 7). Discrimination of the model for MI and other ischemic heart disease (c-statistics 0.58 and 0.60, respectively) was poorer than that for other outcomes (c-statistics ranging from 0.66 to 0.72).

The UKPDS-OM2 substantially overpredicted risks of key CV outcomes and death in people with T2D in ASCEND. Appropriate adjustments or a new model may be required for assessments of long-term effects of treatments in contemporary T2D cohorts.

The alarming rise in the worldwide prevalence of obesity and associated type 2 diabetes mellitus (T2DM) have reached epidemic portions. Diabetes in its many forms and T2DM have different physiological backgrounds and are difficult to classify. Bariatric surgery (BS) is considered the most effective treatment for obesity in terms of weight loss and comorbidity resolution, improves diabetes, and has been proven superior to medical management for the treatment of diabetes. The term metabolic surgery (MS) describes bariatric surgical procedures used primarily to treat T2DM and related metabolic conditions. MS is the most effective means of obtaining substantial and durable weight loss in individuals with obesity. Originally, BS was used as an alternative weight-loss therapy for patients with severe obesity, but clinical data revealed its metabolic benefits in patients with T2DM. MS is more effective than lifestyle or medical management in achieving glycaemic control, sustained weight loss, and reducing diabetes comorbidities. New guidelines for T2DM expand the use of MS to patients with a lower body mass index.Evidence has shown that endocrine changes resulting from BS translate into metabolic benefits that improve the comorbid conditions associated with obesity, such as hypertension, dyslipidemia, and T2DM. Other changes include bacterial flora rearrangement, bile acids secretion, and adipose tissue effect.This review aims to examine the physiological mechanisms in diabetes, risks for complications, the effects of bariatric and metabolic surgery and will shed light on whether diabetes should be reclassified.

My Diabetes My Way (MDMW) is Scotland's interactive website and mobile app for people with diabetes and their caregivers. It contains multimedia resources for diabetes education and offers access to electronic personal health records. This study aims to assess the cost-utility of MDMW compared with routine diabetes care in people with type 2 diabetes who do not use insulin.

Analysis used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model 2. Clinical parameters of MDMW users (n = 2576) were compared with a matched cohort of individuals receiving routine care alone (n = 11 628). Matching criteria: age, diabetes duration, sex, and socioeconomic status. Impact on life expectancy, quality-adjusted life years (QALYs), and costs of treatment and complications were simulated over ten years, including a 10% sensitivity analysis.

MDMW cohort: 1670 (64.8%) men; average age 64.3 years; duration of diabetes 5.5 years. 906 (35.2%) women: average age 61.6 years; duration 4.7 years. The cumulative mean QALY (95% CI) gain: 0.054 (0.044-0.062) years. Mean difference in cost: -£118.72 (-£150.16 to -£54.16) over ten years. Increasing MDMW costs (10%): -£50.49 (-£82.24-£14.14). Decreasing MDMW costs (10%): -£186.95 (-£218.53 to -£122.51).

MDMW is "dominant" over usual care (cost-saving and life improving) in supporting self-management in people with type 2 diabetes not treated with insulin. Wider use may result in significant cost savings through delay or reduction of long-term complications and improved QALYs in Scotland and other countries. MDMW may be among the most cost-effective interventions currently available to support diabetes.