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An increase in visceral fat is associated with an increase in insulin resistance, so reducing body fat mass through exercise may help alleviate type 2 diabetes mellitus (T2DM). The current meta-analysis evaluated the effect of changes in body fat via an intervention of regular exercise on hemoglobin A1c (HbA1c) in patients with T2DM. The inclusion criteria were randomized controlled trials involving adults with T2DM, intervention involving exercise alone, an overall duration of intervention ≥12 weeks, and reporting HbA1c and body fat mass. The mean differences (MDs) were defined as the MD between the exercise group and the control group, and the MDs in HbA1c (in percentage) and body fat mass (in kilograms) were calculated. All MDs in HbA1c were pooled as overall effects. A meta-regression analysis was performed to evaluate the relationship between the MD in the body fat mass (in kilograms) and the MD in HbA1c. Twenty studies (1,134 subjects) were analyzed. The pooled MD in HbA1c (in percentage) decreased significantly (−0.4; 95% confidence interval [−0.5, −0.3]) but contained significant heterogeneity (Q = 52.7, p <.01; I2 = 41.6%). A meta-regression analysis showed that a decrease in the MD in body fat mass was significantly associated with a decrease in the MD in HbA1c (R2 = 80.0%) and heterogeneity decreased (Q = 27.3, p =.61; I2 = 11.9%), and a reduction in body fat mass of 1 kg was estimated to decrease the HbA1c (%) by approximately 0.2. The current study suggested that a decrease in HbA1c due to regular exercise depends on a reduction in body fat mass in patients with T2DM. [ABSTRACT FROM AUTHOR]

Summary: Background: There are limited data on the prevalence and treatment of at‐risk metabolic dysfunction‐associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States. Aim: To estimate the prevalence of at‐risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies. Methods: This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction‐associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis. Results: We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at‐risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co‐existing T2DM and obesity, the prevalence of MASLD, at‐risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively). Conclusion: Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at‐risk MASH and cirrhosis is high, posing a significant risk for liver‐related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH‐related fibrosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Cotadutide is a dual GLP‐1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP‐1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585). Experimental Approach: The cotadutide PK‐4GI systems model was calibrated to clinical data by re‐estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP‐1 and glucagon receptor agonistic effects on glucose. Key Results: Cotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP‐1 receptor‐mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200‐μg cotadutide dose. Conclusion and Implications: The 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP‐1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds. [ABSTRACT FROM AUTHOR]

Metformin (MET) and sitagliptin (STG) are widely used as the first-line and long-term oral hypoglycemic agents for managing type 2 diabetes mellitus (T2DM). However, the current lack of convenient and rapid measurement methods poses a challenge for individualized management. This study developed a point-of-care (POC) assay method utilizing a miniature mass spectrometer, enabling rapid and accurate quantification of MET and STG concentrations in human blood and urine. By combining the miniature mass spectrometer with paper spray ionization, this method simplifies the process into three to four steps, requires minimal amounts of bodily fluids (50 μL of blood and 2 μL of urine), and is able to obtain quantification results within approximately 2 min. Stable isotope-labeled internal standards were employed to enhance the accuracy and stability of measurement. The MS/MS responses exhibited good linear relationship with concentration, with relative standard deviations (RSDs) below 25%. It has the potential to provide immediate treatment feedback and decision support for patients and healthcare professionals in clinical practice. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions The management of patients with type 2 diabetes is asynchronous, i.e. not coordinated in time, resulting in delayed access to care and low use of guideline‐directed medical therapy (GDMT).We retrospectively analysed consecutive patients assessed in the ‘synchronized’ DECIDE‐CV clinic. In this outpatient clinic, patients with type 2 diabetes and cardiovascular or chronic kidney disease are simultaneously assessed by an endocrinologist, cardiologist and nephrologist in the same visit. The primary outcome was use of GDMT before and after the assessment in the clinic, including sodium‐glucose cotransporter 2 inhibitors, glucagon‐like peptide 1 receptor agonists, renin‐angiotensin system blockers and mineralocorticoid receptor antagonists. Secondary outcomes included the baseline‐to‐last‐visit change in surrogate laboratory biomarkers.The first 232 patients evaluated in the clinic were included. The mean age was 67 ± 12 years, 69% were men and 92% had diabetes. In total, 73% of patients had atherosclerotic cardiovascular disease, 65% heart failure, 56% chronic kidney disease and 59% had a urinary albumin‐to‐creatinine ratio ≥30 mg/g. There was a significant increase in the use of GDMT:sodium‐glucose cotransporter 2 inhibitors (from 44% to 87% of patients), glucagon‐like peptide 1 receptor agonists (from 8% to 45%), renin‐angiotensin system blockers (from 77% to 91%) and mineralocorticoid receptor antagonists (from 25% to 45%) (p < .01 for all). Among patients with paired laboratory data, glycated haemoglobin, urinary albumin‐to‐creatinine ratio and N‐terminal proB‐type natriuretic peptide levels significantly dropped from baseline (p < .05 for all).Joint assessment of patients with diabetes in a synchronized cardiometabolic clinic holds promise for enhancing GDMT use and has led to significant reductions in surrogate cardiovascular and renal laboratory biomarkers. [ABSTRACT FROM AUTHOR]

Background: Diabetes control is poor globally and leads to burdensome microvascular and macrovascular complications. We aimed to assess post hoc between-group differences in sustained risk factor control and macrovascular and microvascular endpoints at 6.5 years in the Center for cArdiovascular Risk Reduction in South Asia (CARRS) randomized trial. Methods and findings: This parallel group individual randomized clinical trial was performed at 10 outpatient diabetes clinics in India and Pakistan from January 2011 through September 2019. A total of 1,146 patients with poorly controlled type 2 diabetes (HbA1c ≥8% and systolic BP ≥140 mm Hg and/or LDL-cholesterol ≥130 mg/dl) were randomized to a multicomponent quality improvement (QI) strategy (trained nonphysician care coordinator to facilitate care for patients and clinical decision support system for physicians) or usual care. At 2.5 years, compared to usual care, those receiving the QI strategy were significantly more likely to achieve multiple risk factor control. Six clinics continued, while 4 clinics discontinued implementing the QI strategy for an additional 4-year follow-up (overall median 6.5 years follow-up). In this post hoc analysis, using intention-to-treat, we examined between-group differences in multiple risk factor control (HbA1c <7% plus systolic BP <130 mm Hg and/or LDL-cholesterol <100 mg/dl) and first macrovascular endpoints (nonfatal myocardial infarction, nonfatal stroke, death, revascularization [angioplasty or coronary artery bypass graft]), which were coprimary outcomes. We also examined secondary outcomes, namely, single risk factor control, first microvascular endpoints (retinopathy, nephropathy, neuropathy), and composite first macrovascular plus microvascular events (which also included amputation and all-cause mortality) by treatment group and whether QI strategy implementation was continued over 6.5 years. At 6.5 years, assessment data were available for 854 participants (74.5%; n = 417 [intervention]; n = 437 [usual care]). In terms of sociodemographic and clinical characteristics, participants in the intervention and usual care groups were similar and participants at sites that continued were no different to participants at sites that discontinued intervention implementation. Patients in the intervention arm were more likely to exhibit sustained multiple risk factor control than usual care (relative risk: 1.79; 95% confidence interval [CI], 1.45, 2.20), p < 0.001. Cumulatively, there were 233 (40.5%) first microvascular and macrovascular events in intervention and 274 (48.0%) in usual care patients (absolute risk reduction: 7.5% [95% CI: −13.2, −1.7], p = 0.01; hazard ratio [HR] = 0.72 [95% CI: 0.61, 0.86]), p < 0.001. Patients in the intervention arm experienced lower incidence of first microvascular endpoints (HR = 0.68 [95% CI: 0.56, 0.83), p < 0.001, but there was no evidence of between-group differences in first macrovascular events. Beneficial effects on microvascular and composite vascular outcomes were observed in sites that continued, but not sites that discontinued the intervention. Conclusions: In urban South Asian clinics, a multicomponent QI strategy led to sustained multiple risk factor control and between-group differences in microvascular, but not macrovascular, endpoints. Between-group reductions in vascular outcomes at 6.5 years were observed only at sites that continued the QI intervention, suggesting that practice change needs to be maintained for better population health of people with diabetes. Trial registration: ClinicalTrials.govNCT01212328. Nikhil Tandon and colleagues explore the impact of a quality improvement strategy for patients with type 2 diabetes 6.5 years after its implementation for the CARRS randomised trial. Author summary: Why was this study done?: Data on whether improvements in diabetes care goal achievement can be sustained (>5 years) with quality improvement (QI) strategies are lacking from low- and middle-income countries (LMICs). Prior studies of QI strategies to improve care goal achievement among people with diabetes from high-income countries reported modest benefits in blood glucose, blood pressure, and lipids, but the effects of these improvements on reducing vascular complications and deaths related to diabetes are unknown. What did the researchers do and find?: In the Center for cArdiovascular Risk Reduction in South Asia (CARRS) randomised trial of 1,146 patients with type 2 diabetes attending 10 diverse diabetes clinics in India and Pakistan, the QI strategy was associated with benefits on diabetes care goals (HbA1c <7% plus systolic BP <130 mm Hg and/or LDL-cholesterol <100 mg/dl) at 2.5 years after randomization. Four clinics discontinued implementation, while 6 clinics continued to implement the QI strategy for an additional 4 years. This report assesses whether benefits were sustained and reduced vascular complications and deaths associated with diabetes at 6.5 years. Patients receiving the QI strategy, compared to those receiving usual care, experienced sustained benefits on diabetes care goals and less microvascular endpoints (eye, kidney, and nerve diseases) at 6.5 years after randomization. Total macrovascular and microvascular events were also lower in those receiving the QI strategy, and this was only observed at sites that continued implementation of the QI strategy for 6.5 years. What do these findings mean?: These findings add to our knowledge of the long-term effects of multicomponent QI strategies in sustaining multiple risk factor control and reducing combined vascular events compared to usual care in resource-limited settings. In view of these findings, clinical decision support and trained nonphysician health workers may be important QI strategies to consider integrating into India's healthcare system to improve diabetes care quality and reduce morbidity and mortality. One limitation of the study is that the tertiary care facilities included in the CARRS trial may not be generalizable across LMICs. [ABSTRACT FROM AUTHOR]

Aim Materials and Methods Results Conclusions To assess the differential association of risk factors with severe and non‐severe hypoglycaemia.The Hypoglycaemia Assessment Tool study evaluated the risk of hypoglycaemia over a 4‐week period in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) on insulin in 24 countries. Negative binomial regressions were applied to examine the associations of several risk factors with severe and non‐severe hypoglycaemia.The median age was 41 years in 5949 patients with T1D and 62 years in 12 914 patients with T2D. The 4‐week rates of non‐severe hypoglycaemic were 5.57 and 1.40 episodes per person in T1D and T2D, respectively; the corresponding rates for severe hypoglycaemia were 0.94 and 0.30. The excess risk was 42% higher for severe than non‐severe hypoglycaemia in females versus males with T2D; 27% higher in patients with T2D with versus without a continuous glucose monitoring (CGM); and 47% lower in patients with T1D with versus without an insulin pump. The excess risk also differed across geographical areas and was marginally lower for severe than non‐severe hypoglycaemia for higher values of HbA1c in patients with T2D. Associations with severity of hypoglycaemia were not different for age, diabetes and insulin therapy duration, previous hypoglycaemic episodes and insulin regimen.The risk of severe versus non‐severe hypoglycaemia differs in patients with T1D and T2D; sex, the use of a CGM and insulin pump, and geographical areas were differently associated with one type of hypoglycaemia than the other. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions To explore biomarkers that can predict the response of type 2 diabetes (T2D) patients to metformin at an early stage to provide better treatment for T2D.T2D patients with (responders) or without response (non‐responders) to metformin were recruited, and their serum samples were used for metabolomic analysis to identify candidate biomarkers. Moreover, the efficacy of metformin was verified by insulin‐resistant mice, and the candidate biomarkers were verified to determine the biomarkers. Five different machine learning methods were used to construct the integrated biomarker profiling (IBP) with the biomarkers to predict the response of T2D patients to metformin.A total of 73 responders and 63 non‐responders were recruited, and 88 differential metabolites were identified in the serum samples. After being verified in mice, 19 of the 88 were considered as candidate biomarkers. Next, after metformin regulation, nine candidate biomarkers were confirmed as the biomarkers. After comparing five machine learning models, the nine biomarkers were constructed into the IBP for predicting the response of T2D patients to metformin based on the Naïve Bayes classifier, which was verified with an accuracy of 89.70%.The IBP composed of nine biomarkers can be used to predict the response of T2D patients to metformin, enabling clinicians to start a combined medication strategy as soon as possible if T2D patients do not respond to metformin. [ABSTRACT FROM AUTHOR]

Summary: Background: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is currently the most common chronic liver disease and an important cause of cirrhosis and hepatocellular carcinoma. It is strongly associated with type 2 diabetes and obesity. Because of the huge number of patients at risk of MASLD, it is imperative to use non‐invasive tests appropriately. Aims: To provide a narrative review on the performance and limitations of non‐invasive tests, with a special emphasis on the impact of diabetes and obesity. Methods: We searched PubMed and Cochrane databases for articles published from 1990 to August 2023. Results: Abdominal ultrasonography remains the primary method to diagnose hepatic steatosis, while magnetic resonance imaging proton density fat fraction is currently the gold standard to quantify steatosis. Simple fibrosis scores such as the Fibrosis‐4 index are well suited as initial assessment in primary care and non‐hepatology settings to rule out advanced fibrosis and future risk of liver‐related complications. However, because of its low positive predictive value, an abnormal test should be followed by specific blood (e.g. Enhanced Liver Fibrosis score) or imaging biomarkers (e.g. vibration‐controlled transient elastography and magnetic resonance elastography) of fibrosis. Some non‐invasive tests of fibrosis appear to be less accurate in patients with diabetes. Obesity also affects the performance of abdominal ultrasonography and transient elastography, whereas magnetic resonance imaging may not be feasible in some patients with severe obesity. Conclusions: This article highlights issues surrounding the clinical application of non‐invasive tests for MASLD in patients with type 2 diabetes and obesity. [ABSTRACT FROM AUTHOR]

Summary: Background: The current obesity pandemic has given rise to associated comorbidities and complications, including type 2 diabetes and metabolic dysfunction‐associated steatotic liver disease (MASLD). During the last decade, certain glucagon‐like peptide 1 receptor agonists (GLP‐1RA), originally developed as antihyperglycemic drugs, also demonstrated efficacy for weight loss. Aims: To review shared pathophysiologic features of common metabolic diseases and compare therapeutic strategies to reduce body weight and related complications. Methods: We performed an extensive literature research to describe the effects of lifestyle modification, first‐generation anti‐obesity drugs, and GLP‐1RA on weight loss in humans with obesity, type 2 diabetes and MASLD. Results: Until recently, treatment of obesity has been limited to lifestyle modification, which offer moderate degree and sustainability of weight loss. The few approved first‐generation anti‐obesity drugs are either limited to short term use or to certain forms of obesity. Some GLP‐1RA significantly decrease caloric intake and body weight. Liraglutide and semaglutide have therefore been approved for treating people with obesity. They also lead to a reduction of hepatic fat content and inflammation in people with biopsy‐confirmed MASLD. Possible limitations comprise adverse effects, treatment adherence and persistence. Conclusion: Certain GLP‐1RA are superior to lifestyle modification and first‐generation anti‐obesity drugs in inducing weight loss. They have therefore markedly changed the portfolio of obesity treatment with additional beneficial effects on steatotic liver disease. [ABSTRACT FROM AUTHOR]

Purpose: The aim of our study was to investigate to what degree clinical characteristics can contribute to incidence and structure of pregnancy and childbirth complications in women with diabetes, and to reveal key risk factors for adverse outcomes. Methods: We conducted a retrospective single-center cohort study from January 2008 through December 2017, including 3069 singleton pregnancies, affected by type 1 diabetes (T1D, n = 498), type 2 diabetes (T2D, n = 214), and gestational diabetes mellitus (GDM, n = 2357). Results: More than 10 years duration of T1D associated with increased risk for preterm birth (RR 2.03, 95% CI 1.28–3.20) and preeclampsia (RR 1.57, 95% CI 1.09–2.26). Diabetic nephropathy, same as diabetic proliferative retinopathy, was associated with increased risk of C-section, preeclampsia development, SGA delivery. In patients with T1D who received CSII (12%), we do not report superior outcomes compared to MDI. Pre-pregnancy HbA1c level less than 6.5% reduced the risk of preeclampsia for T1D (RR 0.28, 95% CI 0.19–0.67) and risk of LGA birth for T2D (RR 0.43, 95% CI 0.19–0.92). Achieving glycemic target values by full-term pregnancy reduced the risk of excessive fetal adiposity (RR 0.81 for T1D, RR 0.39 for T2D). For T2D and GDM, the leading risk factors were obesity and chronic hypertension. For patients with GDM, insulin administration and early diagnosis of GDM were the significant risk factors for adverse outcomes. Conclusion: Diabetes during pregnancy is challenging for the clinician, but optimizing glycemic control, treatment regimens, and close attention to comorbidities can help to reduce the risks and ensure appropriate quality diabetes management. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus and depression are serious common diseases, and the number of people with both conditions is rising steadily. Depression in people with diabetes mellitus results in poorer prognosis through different mechanisms. On the other hand, the presence of diabetes in individuals with depression increases functional impairment that is associated with depression. Aims: The study aimed to assess the prevalence and factors associated with depression among adults with type 2 diabetes mellitus attending a diabetes clinic in Cairo, Egypt. Methods: A cross-sectional study was conducted among adult patients with diabetes type 2 attending a diabetes clinic in the endocrinology department in Ain Shams University Teaching Hospital, Cairo, Egypt. Data were collected through face-to-face interviews by trained psychiatrists and from patients' records. Results: The prevalence of depression among diabetic patients was 21.8% (95% CI [15.6%, 29.1%]). Depression was more common among younger age groups and those with a higher level of education. There was no significant difference between those with lifetime depression compared to those without depression regarding physical health complications. Conclusions: The prevalence of depression among patients with type 2 diabetes is high. Given the impact of co-morbid diabetes and depression, diabetic patients should be routinely screened for the latter condition. [ABSTRACT FROM AUTHOR]

Background: Diabetes is one of the main risk factors for developing mild cognitive impairment (MCI) and Alzheimer's disease. Most studies have demonstrated a worse performance in executive function, verbal fluency, and information processing speed in patients with diabetes. Objective: To assess the cognitive functioning of persons with type 2 diabetes and amnesic mild cognitive impairment (aMCI-T2DM) compared to persons with aMCI without diabetes and persons without diabetes or aMCI as controls, to understand the role of diabetes in the neuropsychological profile. Methods: Cross-sectional study involving a sample of 83 patients, ranging in age from 61 to 85 years and divided into three groups: aMCI-T2DM (27 patients), aMCI (29 patients), Controls (27 individuals). All the participants undertook an exhaustive neuropsychological assessment (auditory-verbal and visual memory, attention, information processing speed, language, executive function, and depression). Results: Both groups of aMCI patients performed significantly worse than the controls in all the neuropsychological tests. A significant linear tendency (p trend < 0.05) was found between groups, with the aMCI-T2DM group presenting worse results in global cognition assessed by the Mini-Mental State Examination and Montreal Cognitive Assessment; Rey-Osterrieth Complex Figure Test; Auditory Verbal Learning Test; Trail Making Test A and B, Verbal Fluency Test, and Hamilton Depression Rating Scale. Conclusions: aMCI patients with or without diabetes showed worse cognitive function compared to persons without diabetes or aMCI. Additionally, aMCI patients without T2DM presented a different cognitive profile than aMCI patients with T2DM, which tended towards presenting worse cognitive functions such as global cognition, memory, attention, executive function, and language. [ABSTRACT FROM AUTHOR]

Background: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. Objective: The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1–40 and Aβ1–42 concentrations in individuals with T2D and matched controls. Methods: Ten participants with T2D and 11 controls (median age, 69 years; range, 66–72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1–40, Aβ1–42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1–40 and Aβ1–42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. Results: At baseline, Aβ1–40 and Aβ1–42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1–40: p = 0.034, Aβ1–42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Conclusions: Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D. [ABSTRACT FROM AUTHOR]

A healthy lifestyle comprising regular physical activity and an adequate diet is imperative for the prevention of non‐communicable diseases such as hypertension and some cancers. Advances in information computer technology offer the opportunity to provide personalised lifestyle advice directly to the individual through devices such as smartphones or tablets. The overall aim of the PROTEIN project (Wilson‐Barnes et al., 2021) was to develop a smartphone application that could provide tailored and dynamic nutrition and physical activity advice directly to the individual in real time. However, to create this mobile health (m‐health) smartphone application, a knowledge base of reference ranges for macro‐/micronutrient intake, anthropometry, biochemical, physiological and sleep parameters was required to underpin the parameters of the recommender systems. Therefore, the principal aim of this emerging research paper is to describe the process by which experts in nutrition and physiology from the PROTEIN consortium collaborated to develop the nutritional and physical activity requirements, based upon existing recommendations, for 10 separate population groups living within the EU including, but not limited to healthy adults, adults with type 2 diabetes mellitus, cardiovascular disease, excess weight, obesity and iron deficiency anaemia. A secondary aim is to describe the development of a library of 24‐h meal plans appropriate for the same groups and also encompassing various dietary preferences and allergies. Overall, the consortium devised an extensive nutrition and physical activity knowledge base that is pertinent to 10 separate EU user groups, is available in 7 different languages and is practically implemented via a library of culturally appropriate, 24‐h meal plans. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the association between the number of mental health conditions among individuals with type 2 diabetes (T2D) and healthcare expenditures in the USA. Methods A cross-sectional study was conducted to evaluate the relationship between multiple mental health conditions (0, 1, and 2 or more mental health conditions) among individuals with T2D on healthcare expenditures using data from the 2019 US Medical Expenditure Panel Survey. Key findings A total of 24,091,931 weighted individuals with T2D were included for analysis; 76.8% had no co-occurring mental health conditions, 15.5% had one mental health condition, and 7.7% had two or more mental health conditions. Individuals with one and two or more mental health conditions had significantly greater total healthcare costs (+$7135 and +$7168), office-based costs (+$1196 and +$1483), prescription costs (+$2091 and +$3757), office-based visits (+3.55 and +6.46), and prescriptions fills (+13.97 and +26.77) than individuals with no mental health conditions. Conclusions Individuals with T2D and an increasing number of co-occurring mental health conditions were associated with increased healthcare costs and resource utilization. Underlying mechanisms for this relationship remain unclear, and further investigations are needed to accurately assess the impact this may have on health outcomes. [ABSTRACT FROM AUTHOR]

Objectives Pharmacists' contribution to medication therapy management in type 2 diabetes (T2D) is under-reported in Nigeria. This study evaluated the effectiveness of a pharmacy-based intervention on knowledge, pharmacy refills, medication adherence, and glycemic control among patients with T2D. Methods A two-arm prospective, randomized, controlled trial among 309 T2D patients over 25 weeks duration was conducted in a tertiary hospital. The intervention group (n = 155) received weekly health education and follow-up sent as phone-based short message service (SMS), alongside standard care. Control group (n = 154) received only standard care. Primary (HbA1c reduction) and secondary (refill adherence, knowledge, and medication adherence) outcomes were assessed and compared in both groups at baseline and endline. Key findings Intervention improved glycemic control (HbA1c reduction) directly (t = 8.253, P <.001) and indirectly through improved pharmacy refill adherence as 115 (76%) of the intervention group were refill adherent (Proportion of Days Covered [PDC] > 80%). For controls, mean baseline and endline knowledge scores were 2.798 and 2.816, respectively (t = 1.19092, P >.005), while the intervention group had 2.732 and 4.462, respectively (t = 9.76157, P <.005) on a 5-point Likert scale. Baseline and endline adherence scores for control group were 3.41 and 3.50, respectively (t = 0.92477, P >.05), while the intervention group had 3.35 and 6.72, respectively (t = 17.87981, P <.05) on the 8-point Morisky Medication Adherence Scale (MMAS-8). Conclusion Pharmacist-led intervention significantly improved medication refills, glycemic control, knowledge, and medication adherence. Pharmacists should exploit mobile telephony for health education and follow-up services to improve treatment outcomes in medication therapy management of T2D. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of young ‘MODY’ type 6 is a rare form of monogenic diabetes caused by mutations in neuronal differentiation 1 (NEUROD1). Clinical features vary in a large spectrum in terms of age and body mass index (BMI) at diagnosis. Here, we reported the youngest patient with a NEUROD1 variant to the best of our knowledge. A 2.1-year-old girl was referred to pediatric endocrinology clinic for elevated fasting BG (104 mg/dL) which was detected at another center where she had been evaluated for loss of appetite. Her maternal aunt and uncle had been diagnosed with type 2 diabetes mellitus (DM) at the age of 40 and 45 years; they were obese (BMI: 30.2 and 30.6 kg/m² ). At the age of 3.7 years old, she was hospitalized for buccal cellulitis and plasma glucose concentration was 239 mg/dL at admission. Targeted next-generation sequencing (NGS) was performed considering the stress induced hyperglycemia without serious illness, negative islet cell antibodies and insulin autoantibodies, age at the presentation, and family history of DM. NGS analysis revealed a previously reported heterozygous missense variant in NEUROD1. Segregation studies showed that the identified variant was inherited from her 44-year-old mother with a BMI of 27.2 kg/m² and a normal oral glucose tolerance test. Heterozygous NEUROD1 mutations cause low-penetrant diabetes that is heterogeneous in terms of clinical features as some patients fulfill the classic MODY definition and others are mimicking type 2 DM. Clinical manifestations and family history should be carefully evaluated in patients with stress induced hyperglycemia to identify candidate cases for molecular testing, and proper follow-up should be initiated in affected individuals. [ABSTRACT FROM AUTHOR]

Maturity onset diabetes of the young (MODY) is characterized by noninsulin-dependent diabetes diagnosed before the age of 25 years with an autosomal dominant inheritance. Rare mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene produce a syndrome that resembles MODY. About half of patients diagnosed with MODY type 5 due to HNF1B variants, carry a whole gene deletion, known as 17q12 deletion syndrome. 17q12 deletion syndrome is a rare chromosomal anomaly and is typified by deletion of more than 15 genes, including HNF1B resulting in kidney abnormalities and renal cysts, a diabetes syndrome and neurodevelopmental or neuropsychiatric disorders. A 12-year-old girl was referred after high blood sugar was detected in the hospital where she presented with polyuria and polydipsia, which had persisted for one month. Her serum magnesium (Mg) level was low at 1.5 mg/dL (normal value 1.6-2.6) and glycated hemoglobin was 14% (normal value 3.6-5.8) concurrent with a c-peptide of 1.54 ng/mL (normal value 0.8-4). MODY5 was suspected but the NGS gene panel (ABCC8, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEURODD1, PAX4, PDX1, RFX6, ZFP57, GLIS3, FOXP3, NEUROG3, G6PC2) did not identify any abnormality. During follow-up, her serum Mg remained low (1.2 mg/ dL) together with elevated urinary Mg excretion at 172.5 mg/day. An HNF1B variant was again suspected in a patient with chronic hypomagnesemia with normal basal C peptide level. Abdominal computed tomography and magnetic resonance imaging revealed a 43 mm diameter, cystic lesion in the head of the pancreas, with agenesis of the pancreatic neck, trunk and tail. Genetic testing using a microarray analysis was subsequently performed and a heterozygous deletion at 17q12, including HNF1B, was detected. In case of clinical suspicion of HNF1B variants, further genetic examination using other techniques such as MLPA and CGH array may be required to detect the variant. This is because deletions and duplications may not be detected using next generation screening panel techniques. [ABSTRACT FROM AUTHOR]

Up to 25% of people with type 2 diabetes (T2D) may binge eat which is almost 10 times as many as in the general population. Binge eating is associated with depression, anxiety, and social isolation. Moreover, binge eating may increase the risk of obesity and high blood glucose levels, both of which can accelerate the onset of complications to diabetes and death in people with T2D. Still, little is known about the experiences, needs, and preferences of people with T2D and binge eating that can inform and develop current and future treatment efforts. The aim of the study was therefore to gain in-depth insights into the experiences and biopsychosocial support needs of women and men with T2D and binge eating. Twenty semi-structured individual interviews (65% with females) were conducted and analyzed according to the methodology of Interpretive Description. Four themes were identified: (a) T2D and binge eating: Feeling trapped in a vicious circle; (b) Unwanted outcasts: Responding to continuous criticism; (c) Biomedical relief: Blaming and adjusting the body; and, (d) Silent struggles: Wanting to cease the secrecy. Pertinent to all themes were the guilt, shame, and worries about developing complications that the participants experienced when binge eating despite having T2D. Although binge eating triggered emotional distress, binge eating was at the same time a way of coping with such distress. Implications for treatment and future research are discussed, including the need to systematically assess and address binge eating in routine T2D care. [ABSTRACT FROM AUTHOR]

Growing evidence suggested that individuals with autism spectrum disorder (ASD) associated with stroke and cardiovascular disease (CVD). However, the causal association between ASD and the risk of stroke and CVD remains unclear. To validate this, we performed two-sample Mendelian randomization (MR) and two-step mediation MR analyses, using relevant genetic variants sourced from the largest genome-wide association studies (GWASs). Two-sample MR evidence indicated causal relationships between ASD and any stroke (OR = 1.1184, 95% CI: 1.0302–1.2142, P < 0.01), ischemic stroke (IS) (OR = 1.1157, 95% CI: 1.0237–1.2160, P = 0.01), large-artery atherosclerotic stroke (LAS) (OR = 1.2902, 95% CI: 1.0395–1.6013, P = 0.02), atrial fibrillation (AF) (OR = 1.0820, 95% CI: 1.0019–1.1684, P = 0.04), and heart failure (HF) (OR = 1.1018, 95% CI: 1.0007–1.2132, P = 0.05). Additionally, two-step mediation MR suggested that type 2 diabetes mellitus (T2DM) partially mediated this effect (OR = 1.14, 95%CI: 1.02–1.28, P = 0.03). The mediated proportion were 10.96% (95% CI: 0.58%–12.10%) for any stroke, 11.77% (95% CI: 10.58%–12.97%) for IS, 10.62% (95% CI: 8.04%–13.20%) for LAS, and 7.57% (95% CI: 6.79%–8.36%) for HF. However, no mediated effect was observed between ASD and AF risk. These findings have implications for the development of prevention strategies and interventions for stroke and CVD in patients with ASD. [ABSTRACT FROM AUTHOR]

Background: Data from mechanistic studies suggest flavonoids may benefit glucose metabolism, but their associations with type 2 diabetes (T2D) remain unclear. This study examined the prospective associations of dietary intake of total, classes, and individual flavonoids, as well as their source foods, with T2D in the CArdioVascular disease Association Study (CAVAS). Methods: A total of 16,666 Korean men and women were enrolled at baseline, and 953 were newly diagnosed with T2D over a median follow-up of 5.96 years. Intake of flavonoids was cumulatively averaged using all food frequency questionnaires before the censoring events. A Poisson regression model was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Results: Women with higher total flavonoid, flavonol, isoflavone, and proanthocyanidin intake had a lower risk of T2D (fourth vs. first quartile, IRR 0.62; 95% CI 0.44–0.89; P for linearity and non-linearity < 0.05 for total flavonoids), while in men, flavanones, anthocyanins, and proanthocyanidins, but not total flavonoids, were inversely associated with T2D risk (all P interaction for sex > 0.05). The key source foods contributing to flavonoid intake were also different between men and women, except for apples: tangerines and strawberries in men and green leafy vegetables and soy products in women. Conclusions: A higher intake of total flavonoids, particularly from vegetables, soybeans, and apples, may be associated with lower risk of T2D in women. However, flavonoids from fruits, rather than total flavonoids, may be inversely associated in men. The association between flavonoid intake and the risk of T2D may be contingent upon the dietary sources of flavonoids consumed. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B), a non-transmembrane phosphatase, has a major role in a variety of signalling pathways, including direct negative regulation of classic insulin and leptin signalling pathways, and is implicated in the pathogenesis of several cardiometabolic diseases and cancers. As such, PTP1B has been a therapeutic target for over two decades, with PTP1B inhibitors identified either from natural sources or developed throughout the years. Some of these inhibitors have reached phase I and/or II clinical trials in humans for the treatment of type 2 diabetes mellitus, obesity and/or metastatic breast cancer. In this Review, we summarize the cellular processes and regulation of PTP1B, discuss evidence from in vivo preclinical and human studies of the association between PTP1B and different disorders, and discuss outcomes of clinical trials. We outline challenges associated with the targeting of this phosphatase (which was, until the past few years, viewed as difficult to target), the current state of the field of PTP1B inhibitors (and dual phosphatase inhibitors) and future directions for manipulating the activity of this key metabolic enzyme. This Review summarizes cellular processes and regulation of protein tyrosine phosphatase 1B (PTP1B), discussing evidence from in vivo preclinical and human studies. PTP1B inhibitors, which are being developed for type 2 diabetes mellitus, obesity, rare diseases (such as Rett syndrome) and some cancers, are also discussed. Key points: Protein tyrosine phosphatase 1B (PTP1B) has a key role in the pathogenesis and development of a variety of diseases. Cellular signalling of PTP1B and its implications have been studied extensively; PTP1B has a major role in the regulation of energy expenditure, insulin and leptin signalling, glucose and lipid homeostasis, immune responses, and cancer. Numerous PTP1B inhibitors have been identified from natural sources or designed and synthesized in the past few decades, several of which have reached clinical trials in humans. The main challenges associated with the drug discovery process and development of effective therapeutic agents against PTP1B activity have been specificity, selectivity and bioavailability. Selective and potent therapeutic inhibitors of PTP1B have been reported and could offer a promising potential treatment option for several diseases, such as type 2 diabetes mellitus, obesity, cancer and Rett syndrome. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis (OP) and type 2 diabetes (T2D) are commonly encountered metabolic disorders in clinical practice, but the comorbidity mechanism has not been clarified. This study explored the underlying mechanisms for utilizing bioinformatics methods. Furthermore, it predicted traditional Chinese medicines (TCMs) with preventive and therapeutic effects. Materials and Methods: GSE35958 and GSE43950 were retrieved and downloaded from the GEO database, and differential expression analysis was performed to identify differentially expressed genes (DEGs) with similar expression patterns in OP and T2D. Then, the common DEGs were uploaded to the STRING database to construct a protein interaction network. Enrichment analysis of the screened genes was conducted using R language packages. Relevant TCMs were searched and screened based on gene targets using the Encyclopedia of traditional Chinese medicine (ETCM) database. Molecular docking of active ingredients of the TCMs and related gene targets was performed using AutoDock Vina software. Results: By analyzing the gene expression microarrays, GSE35958 and GSE43950, 34 genes with the same expression pattern shared by OP and T2D were identified. Among these genes, 32 were upregulated and two were downregulated. Protein interaction network analysis revealed that tumor necrosis factor, vascular endothelial growth factor A, and CD44 might play key roles in the co-pathogenesis of T2D and OP. TCMs, including Wolfberry (枸杞), Ginseng (人参), and Yam (山药), were screened based on key genes. Molecular docking results demonstrated binding activity between all active ingredients and the related gene targets. Conclusion: This study explored the potential molecular co-pathogenesis of OP and T2D through bioinformatic analysis and preliminarily predicted traditional herbal medicines that may have preventive and therapeutic effects. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a persistent metabolic condition resulting from insufficient insulin or insulin resistance, which gives rise to diverse complications endangering human well-being. Ramulus Mori (Sangzhi) alkaloids -(SZ-A) have various pharmacological effects, potentially benefiting clinical comprehensive kidney and cardiovascular protection. Nevertheless, the potential protective effect of SZ-A on myocardial injury in individuals with type 2 diabetes mellitus (T2DM) remains unexplored. Materials and Methods: Sprague-Dawley (SD) rats were divided into four groups, including control, model, metformin, and SZ-A. The establishment of the type 2 diabetes model was initiated by injecting streptozotocin (STZ) along with a diet of high glucose and fat. Following a 12-week period of treatment, measurements were taken for heart mass index (HMI), fasting blood glucose (FBG), and 2-h postprandial blood glucose (2hPG). Additionally, serum glycated hemoglobin (HbA1c), indicators of myocardial injury, and oxidative stress were assessed. The expressions of mammalian target of rapamycin (mTOR), p-mTOR, beclin-1, and LC3 in myocardial tissue were detected by Western blot. Results: The administration of SZ-A effectively reduced the levels of HMI, FBG, 2hPG, HbA1c, malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine kinase isoenzymes (CK-MB) in rats with type 2 diabetes while enhancing the activity of superoxide dismutase (SOD). Additionally, SZ-A could improve myocardial tissue arrangement structure and fibrosis degree. Additional analysis revealed that SZ-A suppressed the activation of p-mTOR while enhancing the levels of Beclin-1 and LC3, suggesting that the potential therapeutic impact of SZ-A on myocardial damage could be attributed to its ability to regulate autophagy, thereby mitigating oxidative stress. Conclusion: In summary, the results indicate that SZ-A might possess inhibitory properties against myocardial damage in rats with type 2 diabetes, presenting a potential therapeutic approach in the clinic. [ABSTRACT FROM AUTHOR]

Background: The increasing prevalence of type 2 diabetes mellitus (T2DM) on a global scale has created a pressing demand for novel treatments. Gentianella turkestanorum (Gand.) Holub, a traditional Chinese herbal medicine, has been found to possess hypoglycemic effects. However, the mechanism of its action remains unclear. Objectives: This study was to investigate the impact and mechanism of G. turkestanorum 's water extract (WEG) in reducing insulin resistance (IR) in T2DM. Materials and Methods: Db/db mice were administered WEG for 8 weeks, during which their body weight, blood glucose (BG), oral glucose tolerance test, islet tolerance test, fasting insulin, total cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein were monitored. Additionally, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in db/db mice were measured using enzyme-linked immunosorbent assay (ELISA). The study also evaluated the impact of WEG on liver injury through hematoxylin-eosin staining. The expression levels of key proteins and genes in both insulin signaling and inflammation-related pathways were detected using western blotting and real-time quantitative polymerase chain reaction. Results: WEG has the potential to regulate glycolipid metabolism, reduce inflammation, and alleviate IR. The mechanism of action may involve promoting the insulin signaling pathway and inhibiting inflammation. Conclusion: Gentianella turkestanorum could be a viable treatment option for T2DM and IR. [ABSTRACT FROM AUTHOR]

Maintaining the proteome is crucial to retaining cell functionality and response to multiple intrinsic and extrinsic stressors. Protein misfolding increased the endoplasmic reticulum (ER) stress and activated the adaptive unfolded protein response (UPR) to restore cell homeostasis. Apoptosis occurs when ER stress is prolonged or the adaptive response fails. In healthy young cells, the ratio of protein folding machinery to quantities of misfolded proteins is balanced under normal circumstances. However, the age-related deterioration of the complex systems for handling protein misfolding is accompanied by ageing-related disruption of protein homeostasis, which results in the build-up of misfolded and aggregated proteins. This ultimately results in decreased cell viability and forms the basis of common age-related diseases called protein misfolding diseases. Proteins or protein fragments convert from their ordinarily soluble forms to insoluble fibrils or plaques in many of these disorders, which build up in various organs such as the liver, brain, or spleen. Alzheimer's, Parkinson's, type II diabetes, and cancer are diseases in this group commonly manifest in later life. Thus, protein misfolding and its prevention by chaperones and different degradation paths are becoming understood from molecular perspectives. Proteodynamics information will likely affect future interventional techniques to combat cellular stress and support healthy ageing by avoiding and treating protein conformational disorders. This review provides an overview of the diverse proteostasis machinery, protein misfolding, and ER stress involvement, which activates the UPR sensors. Here, we will discuss the crosstalk between protein misfolding and ER stress and their role in developing age-related diseases. • Proteostasis is emerging as a fundamental process that is altered during ageing. • Protein misfolding and ER stress functionally contributes to the ageing process. • Protein homeostasis hold therapeutic promise for delaying many age-onset diseases. • Understanding misfolding will open new ways in attaining healthy ageing & longevity. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to estimate the prevalence of potentially inappropriate prescriptions (PIPs) in patients starting their first noninsulin antidiabetic treatment (NIAD) using two explicit process measures of the appropriateness of prescribing in UK primary care, stratified by age and polypharmacy status. Methods: A descriptive cohort study between 2016 and 2019 was conducted to assess PIPs in patients aged ≥45 years at the start of their first NIAD, stratified by age and polypharmacy status. The American Geriatrics Society Beers criteria 2015 was used for older (≥65 years) patients and the Prescribing Optimally in Middle‐age People's Treatments criteria was used for middle‐aged (45‐64 years) patients. Prevalence of overall PIPs and individual PIPs criteria was reported using the IQVIA Medical Research Data incorporating THIN, a Cegedim Database of anonymized electronic health records in the UK. Results: Among 28 604 patients initiating NIADs, 18 494 (64.7%) received polypharmacy. In older and middle‐aged patients with polypharmacy, 39.6% and 22.7%, respectively, received ≥1 PIP. At the individual PIP level, long‐term proton pump inhibitors (PPI) use was the most frequent PIP among older adults, and strong opioid without laxatives was the most frequent PIP in middle‐aged patients with polypharmacy (11.1% and 4.1%, respectively). Conclusions: This study revealed that patients starting NIAD treatment receiving polypharmacy have the potential for pharmacotherapy optimization. [ABSTRACT FROM AUTHOR]

To analyse the mechanisms at play in the adjudications made by professionals and socially vulnerable patients with type 2 diabetes about their eligibility for care. The study included 14 patients and 10 health professionals in seven general practice surgeries in deprived areas in Greater Copenhagen. The study data consist of 17 semi-structured interviews with patients and 22 with health professionals immediately after observation of 23 consultations. Our analytical approach was inspired by Systematic Text Condensation and the concept of 'candidacy' for access to health care. Adjudications of patients not being candidates for services were common, but we also found that both patients and health professionals worked to align the services to the needs of the patients. This could include using services differently than was intended by the providers or by changing routines to make it easier for patients to use the services. We discuss these processes as 'tinkering'. This usually implies that the best individual solution for the patient is aimed for, and in this study, the best solution sometimes meant not focusing on diabetes. The study adds to existing knowledge about access to services for socially vulnerable patients by demonstrating that both patients and professionals in general practice engage in tinkering processes to make services work. Unequal use and benefits of health services play a significant role in relation to social inequality in health Flexibility in services and alternatives to school-like rehabilitation are needed to reduce inequality in access to health care Patients were sometimes judged as unsuitable for available routine services, but professionals 'tinkered' with services to make them fit Adaptation of services by professionals in general practice implies a longer time frame for obtaining goals [ABSTRACT FROM AUTHOR]

Peripheral neuropathy is one of the most common complications of type 2 diabetes, which can lead to impaired balance and walking. Innovative footwear devices designed to stimulate foot sensory receptors, such as vibrating insoles, could offer a new route to improve motor impairments in people with diabetic peripheral neuropathy (DPN). Does wearing vibrating insoles for the first time alter measures of balance, walking, and ankle-foot muscle activity, in people with DPN? A randomised cross-over study was conducted with 18 ambulant men and women with a diagnosis of DPN. Participants performed tests of standing balance (Bertec® force platform) under four conditions (foam/firm surface, eyes open/closed) and level-ground walking (GAITRite® instrumented walkway), whilst wearing vibrating and non-vibrating (control) insoles on two separate occasions (one insole/session). Electromyography (EMG) was used to assess soleus, medial gastrocnemius, tibialis anterior, peroneus longus activity during balance tests. Outcomes included centre of pressure (CoP) sway, EMG amplitude, spatiotemporal gait patterns, and Timed Up and Go test. One sample t-tests were used to explore %differences in outcomes between insole conditions. Wearing vibrating insoles led to a reduction (improvement) in CoP elliptical area, when standing on a foam surface with eyes closed, relative to non-vibrating insoles (P =0.03). Applying perceptible vibrations to the soles of the feet also reduced the EMG amplitude in soleus (P =0.01 and P=0.04) and medial gastrocnemius (P =0.03 and P=0.09) when standing with eyes closed on firm and foam surfaces. Our findings of signs of improved balance and altered muscle activity with suprasensory vibrating insoles provides new insights into how these devices can be used to inform innovative rehabilitation approaches in individuals with DPN. This will be strengthened by further research into possible clinical benefits of these devices – given that the effects we detected were small with uncertain clinical meaning. • Wearing vibrating insoles may alter centre of pressure measures during standing. • Perceptible vibrations at the feet reduce the amplitude of plantarflexor activity. • Altered muscle activity may be one underlying mechanism of vibrating insoles. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a heterogeneous disease that can be subdivided on the basis of β-cell function and insulin sensitivity. We investigated the presence, incidence, and progression of diabetic retinopathy (DR) according to subtypes of type 2 diabetes. In a national cohort, we identified three subtypes of type 2 diabetes: classical, hyperinsulinemic, and insulinopenic type 2 diabetes, based on HOMA2 measurements. From the Danish Registry of Diabetic Retinopathy we extracted information on level of DR. We used several national health registries to link information on comorbidity, medications, and laboratory tests. We found individuals with hyperinsulinemic type 2 diabetes were less likely to have DR at entry date compared with those with classical type 2 diabetes, whereas individuals with insulinopenic type 2 diabetes were more likely to have DR. In multivariable Cox regression analysis, individuals with hyperinsulinemic type 2 diabetes had a decreased risk of both incidence and progression of DR compared to those with classical type 2 diabetes. We did not find any clear difference in risk of incident or progression of DR in individuals with insulinopenic compared to classical type 2 diabetes. These findings indicate that subcategorization of type 2 diabetes is important in evaluating the risk of DR. Article Highlights: Type 2 diabetes can be subcategorized on the basis of β-cell function and insulin sensitivity, but little is known about the association of subtypes of type 2 diabetes with risk of diabetic retinopathy (DR). Do individuals with hyperinsulinemic or insulinopenic type 2 diabetes have an increased risk of DR compared with individuals with classical type 2 diabetes? Individuals with hyperinsulinemic type 2 diabetes had almost half the risk of prevalent or incident DR or progression of DR compared with individuals with classical type 2 diabetes. These results suggest that more individualized screening intervals for DR may be possible within subgroups of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Normal-weight individuals with usual-onset type 2 diabetes have reduced β-cell function and greater insulin sensitivity compared with their obese counterparts. The relative contribution of β-cell dysfunction and insulin resistance to young-onset type 2 diabetes (YOD) among normal-weight individuals is not well established. In 44 individuals with YOD (24 with normal weight and 20 with obesity) and 24 healthy control individuals with normoglycemia (12 with normal weight and 12 with obesity), we conducted 2-h 12 mmol/L hyperglycemic clamps to measure acute (0–10 min) and steady-state (100–120 min) insulin and C-peptide responses, as well as insulin sensitivity index. Normal-weight individuals with YOD had lower acute insulin response, steady-state insulin and C-peptide responses, and a higher insulin sensitivity index compared with their obese counterparts with YOD. Compared with BMI-matched healthy control individuals, normal-weight individuals with YOD had lower acute and steady-state insulin and C-peptide responses but a similar insulin sensitivity index. The impairment of steady-state β-cell response relative to healthy control individuals was more pronounced in normal-weight versus obese individuals with YOD. In conclusion, normal-weight Chinese with YOD exhibited worse β-cell function but preserved insulin sensitivity relative to obese individuals with YOD and BMI-matched healthy individuals with normoglycemia. The selection of glucose-lowering therapy should account for pathophysiological differences underlying YOD between normal-weight and obese individuals. Article Highlights: The metabolic architecture of normal-weight young-onset type 2 diabetes (YOD) remains unclear. We investigated the relative contribution of β-cell dysfunction and insulin resistance to normal-weight YOD. Normal-weight individuals with YOD had worse β-cell responses and preserved insulin sensitivity than obese counterparts with YOD and normal-weight healthy control individuals. Our results confirm the pivotal role of β-cell defects in normal-weight YOD and emphasize the importance of preserving β-cell function in this group. [ABSTRACT FROM AUTHOR]

We sought to identify genetic/immunologic contributors of type 2 diabetes (T2D) in an indigenous American community by genotyping all study participants for both high-resolution HLA-DRB1 alleles and SLC16A11 to test their risk and/or protection for T2D. These genes were selected based on independent reports that HLA-DRB1*16:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals with BMI <35 kg/m2. Here, we test the interaction of the two loci with a more complete data set and perform a BMI sensitivity test. We defined the risk protection haplotype of SLC16A11 , T-C-G-T-T , as allele 2 of a diallelic genetic model with three genotypes, SLC16A11*11 , *12 , and *22 , where allele 1 is the wild type. Both earlier findings were confirmed. Together in the same logistic model with BMI ≥35 kg/m2, DRB1*16:02:01 remains protective (odds ratio [OR] 0.73), while SLC16A11 switches from risk to protection (OR 0.57 [ *22 ] and 0.78 [ *12 ]); an added interaction term was statistically significant (OR 0.49 [ *12 ]). Bootstrapped (b = 10,000) statistical power of interaction, 0.4801, yielded a mean OR of 0.43. Sensitivity analysis demonstrated that the interaction is significant in the BMI range of 30–41 kg/m2. To investigate the epistasis, we used the primary function of the HLA-DRB1 molecule, peptide binding and presentation, to search the entire array of 15-mer peptides for both the wild-type and ancient human SLC16A11 molecules for a pattern of strong binding that was associated with risk and protection for T2D. Applying computer binding algorithms suggested that the core peptide at SLC16A11 D127G, FSAFASGLL, might be key for moderating risk for T2D with potential implications for type 1 diabetes. Article Highlights: This study enlarged our sample of high-resolution HLA-DRB1 alleles and 5 individually typed mutations for the SLC16A11 locus and used these to test for protection, risk, and interaction for type 2 diabetes. We confirmed our earlier reports of protection (DRB1*16:02) and risk (SLC16A11) and used all genotypes in a sensitivity analysis for BMI. HLA-DRB1*16:02 was found to be protective, and sensitivity analysis demonstrated that SLC16A11 is a risk in lower BMI strata and protective in higher ones. Epistasis for individuals with DRB1*16:02 and T-C-G-T-T reduces the odds for type 2 diabetes in a BMI range of 30–41 kg/m2, and binding studies implicate core peptide FSAFASGLL. [ABSTRACT FROM AUTHOR]

The postprandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium–glucose cotransporter 1 (SGLT1). This study uses Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1,547 subjects with class II/III obesity from the Atlas Biologique de l'Obésité Sévère cohort, the study uses SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype serves as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-min postload glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results show that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of −0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study links a 1-SD decrease in SGLT1 expression to a Δ30 glucose reduction of −0.097 mmol/L. MR analysis parallels these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decrease of −0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early postload glucose response. This finding has a potential translational impact on managing early glucose response to prevent or treat type 2 diabetes Article Highlights: Loss-of-function variant of SGLT1 is associated with reduced intestinal SGLT1 expression and early postload glucose response. Mendelian randomization supports the causal relationship between intestinal glucose absorption and postprandial glucose. Modulating intestinal SGLT1 expression/function is a promising avenue for the prevention and treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We used MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites, and MRI-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size and enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat. Article Highlights: The relationship between excess adiposity and type 2 diabetes is complex. Can genetic subtypes of adiposity reveal distinct pathways linking adiposity with type 2 diabetes? Higher adiposity increases type 2 diabetes risk via different mechanisms (e.g., cholesterol pathways or inflammation) but decreases risk via other mechanisms (lower liver fat and improved insulin sensitivity, or increased body size and enhanced muscle quality). These insights could improve precision medicine for type 2 diabetes via treating adiposity. [ABSTRACT FROM AUTHOR]

African Americans (AAs) have been underrepresented in polygenic risk score (PRS) studies. Here, we integrated genome-wide data from multiple observational studies on type 2 diabetes (T2D), encompassing a total of 101,987 AAs, to train and optimize an AA-focused T2D PRS (PRSAA), using a Bayesian polygenic modeling method. We further tested the score in three independent studies with a total of 7,275 AAs and compared the PRSAA with other published scores. Results show that a 1-SD increase in the PRSAA was associated with 40–60% increase in the odds of T2D (odds ratio [OR] 1.60, 95% CI 1.37–1.88; OR 1.40, 95% CI 1.16–1.70; and OR 1.45, 95% CI 1.30–1.62) across three testing cohorts. These models captured 1.0–2.6% of the variance (R 2) in T2D on the liability scale. The positive predictive values for three calculated score thresholds (the top 2%, 5%, and 10%) ranged from 14 to 35%. The PRSAA, in general, performed similarly to existing T2D PRS. The need remains for larger data sets to continue to evaluate the utility of within-ancestry scores in the AA population. Article Highlights: This study aimed to better understand the performance of existing and a novel polygenic risk scores (PRS) for type 2 diabetes in African American (AA) populations. A PRS was developed using only genetic data from AA populations (PRSAA) and compared with scores developed using genetic data from other ancestral populations. The performance metrics of the PRSAA were comparable to a published multiancestry PRS developed using training data from much larger study samples. The utility of single-ancestry PRS in AAs should be reevaluated when larger AA training data sets are available. [ABSTRACT FROM AUTHOR]

Acute and chronic sodium–glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP). However, the organ—liver versus kidney—responsible for the increase in EGP has not been identified. In this study, 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) received [3-3H]glucose infusion (to measure total EGP) combined with arterial and renal vein catheterization and para -aminohippuric acid infusion for determination of renal blood flow. Total EGP, net renal arteriovenous balance, and renal glucose production were measured before and 4 h after dapagliflozin (DAPA) and placebo administration. Following DAPA, EGP increased in both T2D and NGT from baseline to 240 min, while there was a significant time-related decrease after placebo in T2D. Renal glucose production at baseline was <5% of basal EGP in both groups and did not change significantly following DAPA in NGT or T2D. Renal glucose uptake (sum of tissue glucose uptake plus glucosuria) increased in both T2D and NGT following DAPA (P < 0.05 vs. placebo). The increase in renal glucose uptake was entirely explained by the increase in glucosuria. A single dose of DAPA significantly increased EGP, which primarily is explained by an increase in hepatic glucose production, establishing the existence of a novel renal-hepatic axis. Article Highlights: Sodium–glucose cotransporter 2 (SGLT2) inhibitors increase endogenous glucose production (EGP) but the organ—liver versus kidney—responsible for the increase in EGP is unknown. Total EGP ([3-3H]glucose), net renal arteriovenous balance (renal vein catheterization), and renal glucose production were measured in 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) before and 4 h after dapagliflozin and placebo administration. Dapagliflozin increased EGP in both T2D and NGT subjects. All of the increase in EGP was derived from an increase in hepatic glucose output. These results establish the existence of a novel renal-hepatic axis. [ABSTRACT FROM AUTHOR]

Adiponectin has vascular anti-inflammatory and protective effects. Although adiponectin protects against the development of albuminuria, historically, the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnCs). In diabetes, eGlx dysfunction occurs before podocyte damage; hence, we hypothesized that adiponectin could protect from eGlx damage to prevent early vascular damage in diabetic kidney disease (DKD). Globular adiponectin (gAd) activated AMPK signaling in human GEnCs through AdipoR1. It significantly reduced eGlx shedding and the tumor necrosis factor-α (TNF-α)–mediated increase in syndecan-4 (SDC4) and MMP2 mRNA expression in GEnCs in vitro. It protected against increased TNF-α mRNA expression in glomeruli isolated from db/db mice and against expression of genes associated with glycocalyx shedding (namely, SDC4, MMP2, and MMP9). In addition, gAd protected against increased glomerular albumin permeability (Ps'alb) in glomeruli isolated from db/db mice when administered intraperitoneally and when applied directly to glomeruli (ex vivo). Ps'alb was inversely correlated with eGlx depth in vivo. In summary, adiponectin restored eGlx depth, which was correlated with improved glomerular barrier function, in diabetes. Article Highlights: Adiponectin protects against diabetic kidney disease (DKD). Understanding its role on glomerular endothelial barrier properties should help formulate a strategic therapeutic approach. This study shows adiponectin protects against endothelial glycocalyx shedding and restores albumin permeability in experimental diabetes. Activation of the glomerular endothelial cell adiponectin signaling pathway may be an early treatment strategy for patients with diabetes who are at risk of DKD. [ABSTRACT FROM AUTHOR]

Sodium–glucose cotransporter 2 inhibitors, efficacious antidiabetic agents that have cardiovascular and renal benefits, can promote pancreatic β-cell regeneration in type 2 diabetic mice. However, the underlying mechanism remains unclear. In this study, we aimed to use multiomics to identify the mediators involved in β-cell regeneration induced by dapagliflozin. We showed that dapagliflozin lowered blood glucose level, upregulated plasma insulin level, and increased islet area in db/db mice. Dapagliflozin reshaped gut microbiota and modulated microbiotic and plasmatic metabolites related to tryptophan metabolism, especially l-tryptophan, in the diabetic mice. Notably, l-tryptophan upregulated the mRNA level of glucagon-like peptide 1 (GLP-1) production–related gene (Gcg and Pcsk1) expression and promoted GLP-1 secretion in cultured mouse intestinal L cells, and it increased the supernatant insulin level in primary human islets, which was eliminated by GPR142 antagonist. Transplant of fecal microbiota from dapagliflozin-treated mice, supplementation of l-tryptophan, or treatment with dapagliflozin upregulated l-tryptophan, GLP-1, and insulin or C-peptide levels and promoted β-cell regeneration in db/db mice. Addition of exendin 9-39, a GLP-1 receptor (GLP-1R) antagonist, or pancreatic Glp1r knockout diminished these beneficial effects. In summary, treatment with dapagliflozin in type 2 diabetic mice promotes β-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism. Article Highlights: Sodium–glucose cotransporter 2 inhibitors, novel and efficacious antidiabetic agents, can preserve β-cell mass in type 2 diabetic animals, but the mechanism remains unclear. We find that dapagliflozin reshapes gut microbiota, improves microbiotic and plasmatic metabolites related to tryptophan metabolism, and increases glucagon-like peptide 1 (GLP-1) production mediated via tryptophan metabolism. GLP-1−GLP-1 receptor signaling participates in the dapagliflozin-induced β-cell regeneration. Our study reveals that the gut microbiota–tryptophan metabolism–GLP-1 axis is a novel mechanism of β-cell regeneration induced by dapagliflozin and provides experimental evidence for its β-cell protection in treating type 2 diabetes. [ABSTRACT FROM AUTHOR]

Epidemiological evidence showed that patients suffering from obesity and T2DM are significantly at higher risk for chronic low-grade inflammation, oxidative stress, nonalcoholic fatty liver (NAFLD) and intestinal flora imbalance. Increasing evidence of pathological characteristics illustrates that some common signaling pathways participate in the occurrence, progression, treatment, and prevention of obesity and T2DM. These signaling pathways contain the pivotal players in glucose and lipid metabolism, e.g., AMPK, PI3K/AKT, FGF21, Hedgehog, Notch, and WNT; the inflammation response, for instance, Nrf2, MAPK, NF- kB, and JAK/STAT. Bioactive compounds from plants have emerged as key food components related to healthy status and disease prevention. They can act as signaling molecules to initiate or mediate signaling transduction that regulates cell function and homeostasis to repair and re-functionalize the damaged tissues and organs. Therefore, it is crucial to continuously investigate bioactive compounds as sources of new pharmaceuticals for obesity and T2DM. This review provides comprehensive information of the commonly shared signaling pathways between obesity and T2DM, and we also summarize the therapeutic bioactive compounds that may serve as anti-obesity and/or anti-diabetes therapeutics by regulating these associated pathways, which contribute to improving glucose and lipid metabolism, attenuating inflammation. [ABSTRACT FROM AUTHOR]

This study aimed to assess the correlation between glycemic status (prediabetes and type 2 diabetes mellitus) and the risk of gastric cancer according to menopausal status. A total of 982,559 pre/peri-menopausal and 1445,419 postmenopausal women aged ≥ 40, who underwent the Korean national health screening in 2009, were included and followed up until 2018. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for development of gastric cancers according to hyperglycemic status in both groups using Cox proportional hazards models. Over a mean follow-up period of 8.3 years, 3259 (0.33%) pre/peri-menopausal women and 13,245 (0.92%) postmenopausal women were diagnosed with gastric cancer. In postmenopausal women, only diabetes mellitus conferred a higher risk of gastric cancer compared to normal glycemic status (HR, 1.15; 95% CI, 1.09–1.20), with an increasing trend of gastric cancers from prediabetes to diabetes (P for trend < 0.001) observed regardless of menopausal status. Obesity, smoking, and heavy alcohol consumption was associated with increased gastric cancer risk mainly in the postmenopausal period. The risk of gastric cancer escalates with deteriorating glycemic status in a dose-response manner. Diabetes mellitus is linked with an elevated risk of gastric cancer in postmenopausal women. [ABSTRACT FROM AUTHOR]

The article discusses the challenges faced by individuals with type 1 diabetes who also struggle with obesity. While advancements in diabetes management have improved glycemic control and quality of life for those with type 1 diabetes, they have also led to weight gain and an increased risk of obesity. This combination of type 1 diabetes and obesity, known as "double diabetes," can lead to further complications and cardiovascular risks. The article highlights the need for evidence-based interventions and guidelines to address the dual treatment of type 1 diabetes and obesity. It also discusses the challenges in lifestyle modification, pharmacotherapy, and bariatric surgery for individuals with type 1 diabetes and obesity. The authors emphasize the importance of further research and a holistic approach to managing both conditions. [Extracted from the article]

Aim: Type 2 diabetes mellitus (T2DM) is one of the most common diseases, and epigenetic modification N6‐methyladenosine (m6A) is essential for transcriptional modulation involved in its development. However, the precise role and landscape of transcriptome‐wide m6A alterations in molecular adaptations after physical exercise have yet to be fully elucidated. Methods: Four‐week‐old male C57BL/6J mice received a high‐fat diet (HFD) for 12 weeks to establish a diabetic state, and HFD mice were simultaneously subjected to physical exercise (HFD + EX). The hepatic RNA m6A methylome was examined, the conjoint MeRIP‐seq and RNA‐seq was performed, and the exercise‐modulated genes were confirmed. Results: Physical exercise significantly ameliorates liver metabolic disorder and triggers a dynamic change in hepatic RNA m6A. By analyzing the distribution of m6A in transcriptomes, an abundance of m6A throughout mRNA transcripts and a pattern of conserved m6A after physical exercise was identified. It is noteworthy that conjoint MeRIP‐seq and RNA‐seq data revealed that both differentially methylated genes and differentially expressed genes were enriched in all stages of the PI3K‐Akt signaling pathway, in particular the upstream nodes of this pathway, which are considered a valuable therapeutic target for T2DM. Moreover, in vivo and in vitro analyses showed that exercise‐mediated methyltransferase Rbm15 positively regulated the expression of two upstream genes (Itga3 and Fgf21) in an m6A‐dependent manner. Conclusion: These findings highlight the pivotal role of the exercise‐induced m6A epigenetic network and contribute insights into the intricate epigenetic mechanism underlying insulin signaling. [ABSTRACT FROM AUTHOR]

Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin‐sensitive tissues post‐prandially, this anabolic hormone restores blood glucose levels to pre‐prandial levels. Maintaining physiological glucose levels thus relies on proper β‐cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type‐specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively "disallowed", including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life‐threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply‐driven rather than demand‐driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β‐cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients. [ABSTRACT FROM AUTHOR]

Type 2 Diabetes (T2D) among older Asian American immigrants (AA) is a growing concern. Asian Americans represent 9% of diagnosed diabetes. Very little is known on how older Asian American immigrants with T2D navigate diabetes management, in particular the role of family support. This qualitative study examines Chinese and Filipino Americans, the two largest Asian subgroups in the US (4.2 million, and 3.6 million, respectively), and family support dynamics among adult children and their parents diagnosed with T2D. Ten dyads (n = 20) made up of adult children and aging parents participated in in-depth and dyadic interviews. Results indicate that family support occurs in a trajectory of stages. The following thematic patterns emerged in these dyads around support: independence, transitions, partnership, and stepping in. The findings point to various supportive stages that Asian American adult children and aging parents with T2D experience and the importance of developing supportive interventions for both adult children and aging parents at these various stages. [ABSTRACT FROM AUTHOR]

1-deoxynojirimycin (DNJ), a piperidine iminosugar analogous to D-glucose, exhibits various biological properties with antidiabetic, antiviral, anti-inflammatory, and antimicrobial effects. N -alkylated DNJ derivatives have been used clinically as medicines for type 2 diabetes and lysosomal storage diseases. DNJ naturally occurs in plants and microbes, and the methods of DNJ production in these organisms have attained stereoselectivity with more environmentally friendly and simpler processes than chemical synthesis. However, the yield of DNJ has to be improved by reinforcing its biosynthetic pathway. This review summarizes the various DNJ-producing species and the production titer of DNJ in plants and microbes. Additionally, it compares the methods used to validate the biosynthesis of DNJ in plants and in microbes. It also covers the application of some DNJ biosynthesis-related genes and the enhancement of DNJ content via metabolic engineering. Finally, this review highlights new biological sources of other iminosugars that can be detected through the knowledge of DNJ biosynthesis. [Display omitted] • Deoxynojirimycin (DNJ) is a piperidine iminosugar with medicinal properties. • DNJ is naturally found in mulberry plants and Bacillus and Streptomyces spp. • DNJ yield can be improved with the discovery of genes involved in its biosynthesis. • Biological production of new iminosugar can be identified via DNJ biosynthetic genes. [ABSTRACT FROM AUTHOR]