-
1.
Understanding Metabolic Memory: A Tale of Two Studies.
Miller, RG, Orchard, TJ
Diabetes. 2020;(3):291-299
-
-
Free full text
-
Abstract
The results of the Diabetes Control and Complications Trial (DCCT) have given rise to much encouragement in the battle to stave off the complications of type 1 diabetes, showing dramatic declines in the development of severe retinopathy, nephropathy, and neuropathy in those treated intensively compared with conventional therapy. Particularly encouraging has been the continuing difference between the two groups despite both having similar HbA1c (∼8%) since the end of DCCT, when 96% of participants entered the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. This continuing relative benefit has been termed "metabolic memory," which implies altered metabolic regulation. Based on evidence from both the Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset type 1 diabetes and DCCT/EDIC, we show that the metabolic memory effect can be largely explained by lower cumulative glycemic exposure in the intensive therapy group, and, on average, the development of complications increases with greater glycemic exposure, irrespective of whether this results from a high exposure for a short time or a lower exposure for a longer time. Thus, there is no need for a concept like "metabolic memory" to explain these observations. Potential mechanisms explaining the cumulative glycemic effect are also briefly discussed.
-
2.
GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes.
Love, KM, Liu, J, Regensteiner, JG, Reusch, JEB, Liu, Z
Journal of diabetes. 2020;(7):488-498
-
-
Free full text
-
Abstract
Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine-tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin-mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon-like peptide 1 (GLP-1) receptors. GLP-1, in addition to its well-characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP-1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP-1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP-1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP-1 in cardiac as well as skeletal muscle function.
-
3.
Role of insulin, adenosine, and adipokine receptors in the foetoplacental vascular dysfunction in gestational diabetes mellitus.
Subiabre, M, Villalobos-Labra, R, Silva, L, Fuentes, G, Toledo, F, Sobrevia, L
Biochimica et biophysica acta. Molecular basis of disease. 2020;(2):165370
Abstract
Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with maternal and foetal hyperglycaemia and altered foetoplacental vascular function. Human foetoplacental microvascular and macrovascular endothelium from GDM pregnancy show increased maximal l-arginine transport capacity via the human cationic amino acid transporter 1 (hCAT-1) isoform and nitric oxide (NO) synthesis by the endothelial NO synthase (eNOS). These alterations are paralleled by lower maximal transport activity of the endogenous nucleoside adenosine via the human equilibrative nucleoside transporter 1 (hENT1) and activation of adenosine receptors. A causal relationship has been described for adenosine-activation of A2A adenosine receptors, hCAT-1, and eNOS activity (i.e. the Adenosine/l-Arginine/Nitric Oxide, ALANO, signalling pathway). Insulin restores these alterations in GDM via activation of insulin receptor A (IR-A) form in the macrovascular but IR-A and IR-B forms in the microcirculation of the human placenta. Adipokines are secreted from adipocytes influencing the foetoplacental metabolic and vascular function. Various adipokines are dysregulated in GDM, with adiponectin and leptin playing major roles. Abnormal plasma concentration of these adipokines and the activation or their receptors are involved in the pathophysiology of GDM. However, involvement of adipokines, adenosine, and insulin receptors and membrane transporters in the aetiology of this disease of pregnancy is unknown. This review focuses on the pathophysiology of insulin and adenosine receptors and l-arginine and adenosine membranes transporters giving an overview of the key adipokines leptin and adiponectin in the foetoplacental vasculature in GDM. This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.
-
4.
Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management.
Cooper, ID, Crofts, CAP, DiNicolantonio, JJ, Malhotra, A, Elliott, B, Kyriakidou, Y, Brookler, KH
Open heart. 2020;(2)
Abstract
Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.
-
5.
Management of Diabetic Ketoacidosis in Children and Adolescents with Type 1 Diabetes Mellitus.
Castellanos, L, Tuffaha, M, Koren, D, Levitsky, LL
Paediatric drugs. 2020;(4):357-367
Abstract
Diabetic ketoacidosis (DKA) is the end result of insulin deficiency in type 1 diabetes mellitus (T1D). Loss of insulin production leads to profound catabolism with increased gluconeogenesis, glycogenolysis, lipolysis, and muscle proteolysis causing hyperglycemia and osmotic diuresis. High levels of counter-regulatory hormones lead to enhanced ketogenesis and the release of 'ketone bodies' into the circulation, which dissociate to release hydrogen ions and cause an overwhelming acidosis. Dehydration, hyperglycemia, and ketoacidosis are the hallmarks of this condition. Treatment is effective repletion of insulin, fluids and electrolytes. Newer approaches to early diagnosis, treatment, and prevention may diminish the risk of DKA and its childhood complications including cerebral edema. However, the potential for some technical and pharmacologic advances in the management of T1D to increase DKA events must be recognized.
-
6.
Effects of Acute Dietary Polyphenols and Post-Meal Physical Activity on Postprandial Metabolism in Adults with Features of the Metabolic Syndrome.
Davis, DW, Navalta, JW, McGinnis, GR, Serafica, R, Izuora, K, Basu, A
Nutrients. 2020;(4)
Abstract
Approximately 22% of U.S. adults and 25% of adults globally have metabolic syndrome (MetS). Key features, such as dysglycemia and dyslipidemia, predict type 2 diabetes, cardiovascular disease, premature disability, and death. Acute supplementation of dietary polyphenols and post-meal physical activity hold promise in improving postprandial dysmetabolism. To our knowledge, no published review has described the effects of either intervention on postprandial glucose, insulin, lipids, and markers of oxidative damage and inflammation in adults with features of MetS. Thus, we conducted this review of controlled clinical trials that provided dietary polyphenols from oils, fruits, teas, and legumes during a dietary challenge, or implemented walking, cycling, and stair climbing and descending after a dietary challenge. Clinical trials were identified using ClinicalTrials.gov, PubMed, and Google Scholar and were published between 2000 and 2019. Dietary polyphenols from extra virgin olive oil, grapes, blackcurrants, strawberries, black tea, and black beans improved postprandial glucose, insulin, and markers of oxidative damage and inflammation, but results were not consistent among clinical trials. Freeze-dried strawberry powder distinctly improved postprandial insulin and markers of oxidative damage and inflammation. Post-meal physical activity attenuated postprandial glucose, but effects on postprandial lipids and markers of oxidative damage and inflammation were inconclusive. Consuming dietary polyphenols with a meal and completing physical activity after a meal may mitigate postprandial dysmetabolism in adults with features of MetS.
-
7.
[Real and misinterpretation of insulin resistance in the clinical practice].
Winkler, G
Orvosi hetilap. 2020;(26):1088-1093
Abstract
Confirming or ruling out the presence of insulin resistance (IR) is one of the most common reasons for referral to non-diabetics in Hungary for diabetes outpatient units. The article overviews the concept of IR, its importance in pathophysiology, the diagnostic capabilities, and its treatment implications. It emphasizes that the decline in insulin activity is a co-morbidity of many diseases and does not, in itself, require detailed examination without other symptoms. If this occurs, it is sufficient to calculate the HOMA-IR value and determine fasting blood glucose and serum insulin levels for information purposes. If it is confirmed as part of a comorbid condition, complex treatment is required. Orv Hetil. 2020; 161(26): 1088-1093.
-
8.
Role of the ketogenic diet in acute neurological diseases.
Arora, N, Mehta, TR
Clinical neurology and neurosurgery. 2020;:105727
Abstract
The current review outlines the role of ketogenic diet (KD) in the management of acute neurological conditions namely traumatic brain injury, ischemic stroke, status epilepticus and primary aggressive brain tumor. An overview of the scientific literature- both clinical and pre-clinical studies is presented along with the proposed mechanism of ketogenic diet. The review also describes different formulations of commercially available ketogenic diets along with the common adverse effects and dosing recommendations.
-
9.
Exogenous Insulin Injection-Induced Stiff-Person Syndrome in a Patient With Latent Autoimmune Diabetes: A Case Report and Literature Review.
Lee, YY, Lin, CW, Chen, IW
Frontiers in endocrinology. 2020;:594
Abstract
Stiff-person syndrome (SPS) is highly associated with anti-glutamic acid decarboxylase (GAD) antibody. However, GAD antibodies alone appear to be insufficient to cause SPS, and they possibly are involved in only part of its pathophysiology. It is suspected that the symptoms of SPS get precipitated by external stimuli. Here, we briefly introduce the case of a patient with latent autoimmune diabetes who developed SPS through the action of subcutaneously injected insulin. A 43-year-old man was diagnosed with diabetes and initially well-controlled with oral hypoglycemic agents but progressed to requiring insulin within 1 year of diagnosis. Two months after the initiation of basal insulin therapy, he presented with abdominal stiffness and painful muscle spasms, involving the lower limbs, which resulted in walking difficulty, and thus, he refused insulin injections thereafter. He had been treated with oral anti-diabetic agents instead of insulin for 10 years until premixed insulin twice daily was started again due to poor diabetes control. Immediately after insulin injection, abdominal muscle rigidity and spasms were noted. When insulin was not administered, frequent episodes of diabetic ketoacidosis occurred. Serum GAD antibody test was positive and there was no positivity for islet antigen-2 antibody. A glucagon stimulation test demonstrated relative insulin deficiency, indicative of latent autoimmune diabetes in adults (LADA). Tolerable muscle rigidity was achieved when the dosage of basal insulin was split into two separate daily injections with lower amounts of units per injection. This case highlights a different form of autoimmune diabetes in SPS. To our knowledge, this is the first report of SPS described shortly after the initiation of insulin therapy that required basal insulin to achieve tolerable muscle symptoms and better glucose control, without the development of diabetic ketoacidosis.
-
10.
Glycemic Monitoring and Management in Advanced Chronic Kidney Disease.
Galindo, RJ, Beck, RW, Scioscia, MF, Umpierrez, GE, Tuttle, KR
Endocrine reviews. 2020;(5):756-74
-
-
Free full text
-
Abstract
Glucose and insulin metabolism in patients with diabetes are profoundly altered by advanced chronic kidney disease (CKD). Risk of hypoglycemia is increased by failure of kidney gluconeogenesis, impaired insulin clearance by the kidney, defective insulin degradation due to uremia, increased erythrocyte glucose uptake during hemodialysis, impaired counterregulatory hormone responses (cortisol, growth hormone), nutritional deprivation, and variability of exposure to oral antihyperglycemic agents and exogenous insulin. Patients with end-stage kidney disease frequently experience wide glycemic excursions, with common occurrences of both hypoglycemia and hyperglycemia. Assessment of glycemia by glycated hemoglobin (HbA1c) is hampered by a variety of CKD-associated conditions that can bias the measure either to the low or high range. Alternative glycemic biomarkers, such as glycated albumin or fructosamine, are not fully validated. Therefore, HbA1c remains the preferred glycemic biomarker despite its limitations. Based on observational data for associations with mortality and risks of hypoglycemia with intensive glycemic control regimens in advanced CKD, an HbA1c range of 7% to 8% appears to be the most favorable. Emerging data on the use of continuous glucose monitoring in this population suggest promise for more precise monitoring and treatment adjustments to permit fine-tuning of glycemic management in patients with diabetes and advanced CKD.