South Asians, known to have more body fat for the same body mass index (BMI), have been shown to be more insulin resistant than Whites.5 6 Previous studies did not find South Asians to have higher ...degrees of insulin deficiency than Whites.7 However, two epidemiological studies in the current issue of BMJ-DRC suggest otherwise.8 9 The first study compared the incidence of T2D in South Asians living in urban India and Pakistan with Blacks and Whites living in urban and suburban areas in the USA.8 South Asian data were obtained from the Cardiometabolic Risk Reduction in South Asia Study that recruited healthy subjects in 2010–2011 and followed them until 2016–2017 with a median follow-up of 4.8 years. The epidemiological data can only provide a correlation and cannot be considered equivalent to the carefully conducted mechanistic studies. ...there are multiple limitations of these data. Insulin resistance and defects in insulin secretion are essential components of the pathophysiology of T2D. ...within any healthy population, those with lower insulin secretion or higher insulin resistance at baseline will be more likely to develop T2D.
Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications
. Epidemiological studies have ...suggested that diabetes is also linked to an increased risk of cancer
. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.
The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, ...diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers.
The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development.
This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes.
This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.
The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by ...the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid-binding protein 4 (FABP4).
-deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted.
The management of hyperglycemia in patients with kidney failure is complex, and the goals and methods regarding glycemic control in chronic kidney disease (CKD) are not clearly defined. Although ...aggressive glycemic control seems to be advantageous in early diabetic nephropathy, outcome data supporting tight glycemic control in patients with advanced CKD (including end-stage renal disease ESRD) are lacking. Challenges in the management of such patients include therapeutic inertia, monitoring difficulties, and the complexity of available treatments. In this article, we review the alterations in glucose homeostasis that occur in kidney failure, current views on the value of glycemic control and issues with its determination, and more recent approaches to monitor or measure glycemic control. Hypoglycemia and treatment options for patients with diabetes and ESRD or earlier stages of CKD also are addressed, discussing the insulin and noninsulin agents that currently are available, along with their indications and contraindications. The article provides information to help clinicians in decision making in order to provide individualized glycemic goals and appropriate therapy for patients with ESRD or earlier stages of CKD.
Euglycemic diabetic ketoacidosis (EDKA) is an emerging complication of diabetes associated with an increasing use of sodium-glucose transporter type 2 (SGLT-2) inhibitor drugs. This review highlights ...the growing incidence of EDKA and its diagnostic challenges due to the absence of hallmark hyperglycemia seen in diabetic ketoacidosis (DKA). The paper presents a classification system for the severity of EDKA, categorizing it into mild, moderate, and severe based on serum pH and bicarbonate levels. Another classification system is proposed to define stages of EDKA based on anion gap and ketones at the time of diagnosis and during the treatment period. A treatment algorithm is proposed to guide clinicians in managing EDKA. This treatment algorithm includes monitoring anion gap and ketones to guide insulin and fluid management, and slower transition to subcutaneous insulin to prevent a relapse. Increased awareness of EDKA is essential for a timely diagnosis because an early diagnosis and treatment can improve clinical outcomes.
Weight variability in diabetes is an emerging risk factor for macrovascular complications and mortality, potentially via increased inflammation. We examined the impact of pre-admission weight cycling ...(WC) on COVID-19-related outcomes, including in-hospital mortality, ICU admission, and mechanical ventilation (MV), using a large multicenter cohort. This study included 277 adults with diabetes hospitalized with COVID-19 (March 2020-February 2021) at 5 university hospitals in the eastern US (COVIDEastDM Consortium) with body weight measurements at 0, 6, and 12 months before admission. Weight change was considered significant if it exceeded 5% in each 6-month interval. The cohort was grouped into four weight categories: unchanged (n=57; reference group), weight loss (WL; n=88), weight gain (WG; n=50) and WC (n=32), and was 54.6% male, 58.6% White, 24.2% Black, 18.5% Hispanic, with mean (SD) age 65.1 (12.6) years and HbA1c 7.7 (2.0)%. During hospitalization, 41.9% subjects were admitted to the ICU, 25.1% received MV, and 15.0% died. Age was the strongest risk factor for mortality (OR = 1.08 95% CI: 1.03-1.13), and the presence of pre-existing comorbidity for both ICU admission (OR = 2.58 1.13-5.90) and MV (OR = 3.89 1.30-11.64). In an adjusted model, WC, but not WL or WG, was associated with ICU admission (OR = 3.09 1.11-8.59) and MV ((OR = 4.59 1.48-14.19), but not with mortality (OR = 3.19 0.76-13.32). The glycemic gap, shown previously to be associated with increased MV and mortality, did not change the relationship between WC and outcomes. The WC group trended toward higher peak ESR (94.3±23.1 ml/h vs. 62.2±33.5 ml/h, P=0.044) and hsCRP levels (150.0±133.9 mg/L vs. 104.1±105.3 mg/L, P=0.142).
Conclusion: Weight cycling is associated with ICU admission and mechanical ventilation in adults with diabetes and COVID-19. Our findings identify a unique vulnerability of individuals with diabetes and recent weight cycling.
Disclosure
Y. Kang: None. R. S. Weinstock: Consultant; Jaeb Center for Health Research, Other Relationship; Wolters Kluwer Health, Research Support; Insulet Corporation, Medtronic, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim Inc., Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Tandem Diabetes Care, Inc., Kowa Pharmaceuticals America, Inc. M. E. Mcdonnell: None. D. C. Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows. A. S. Chaugule: None. R. K. Garg: None. G. Gopalakrishnan: Research Support; Spruce Biosciences, Sparrow Pharmaceuticals Inc, Medtronic. K. Howard: None. J. Lebastchi: None. J. Mitri: Other Relationship; Novo Nordisk, Research Support; Kowa Company, Ltd. N. E. Palermo: Research Support; Dexcom, Inc.
Our consortium previously reported that older age, elevated glycemic gap, higher BMI and DKA on admission predicted mortality in adults with diabetes or stress hyperglycemia (glucose >180 mg/dl twice ...in 24 hrs) admitted with COVID-19 from March 2020 - February 2021 to 5 university hospitals. Here we examine those from this cohort who were readmitted (19.4%) after their initial discharge (Table). Of those readmitted 90.3% were readmitted within 30 days median (IQR) 4 (0, 14) days. Older age, lower eGFR, comorbidities, ICU admission, mechanical ventilation, DKA and longer length of stay during the initial hospitalization were associated with readmission. Higher A1c and admission glucose, diagnosed diabetes, glycemic gap and BMI did not predict increased risk of readmission. Hispanics were less likely to be readmitted. Mortality during readmission was 8.0%. Those who died were older than those who survived (74.9±9.5 vs 65.2±14.4 yrs, p= 0.002) and were more likely to have had DKA during the first hospitalization (p< 0.001). Mortality analyses were limited by the small number of deaths (n=23). In conclusion, in adults with diabetes or stress hyperglycemia hospitalized with COVID-19, older age and non-glycemic comorbidities were associated with the risk of readmission, while glycemic gap and higher A1c were not. These results are important for guiding treatment strategies.
Disclosure
A.S.Chaugule: None. G.P.Westcott: None. R.S.Weinstock: Consultant; Jaeb Center for Health Research, Other Relationship; Wolters Kluwer Health, Research Support; Insulet Corporation, Medtronic, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim Inc., Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Tandem Diabetes Care, Inc., Kowa Pharmaceuticals America, Inc. K.Howard: None. D.C.Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows. M.E.Mcdonnell: None. R.K.Garg: None. G.Gopalakrishnan: Research Support; Spruce Biosciences, Sparrow Pharmaceuticals Inc, Medtronic. J.Mitri: Other Relationship; Novo Nordisk, Research Support; Kowa Company, Ltd. J.Lebastchi: None. N.E.Palermo: Research Support; Dexcom, Inc.
Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological ...relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.
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