Type 2 diabetes mellitus (T2DM) is characterized by a progressive failure of pancreatic β-cell function (BCF) with insulin resistance. Once insulin over-secretion can no longer compensate for the ...degree of insulin resistance, hyperglycemia becomes clinically significant and deterioration of residual β-cell reserve accelerates. This pathophysiology has important therapeutic implications. Ideally, therapy should address the underlying pathology and should be started early along the spectrum of decreasing glucose tolerance in order to prevent or slow β-cell failure and reverse insulin resistance. The development of an optimal treatment strategy for each patient requires accurate diagnostic tools for evaluating the underlying state of glucose tolerance. This review focuses on the most widely used methods for measuring BCF within the context of insulin resistance and includes examples of their use in prediabetes and T2DM, with an emphasis on the most recent therapeutic options (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists). Methods of BCF measurement include the homeostasis model assessment (HOMA); oral glucose tolerance tests, intravenous glucose tolerance tests (IVGTT), and meal tolerance tests; and the hyperglycemic clamp procedure. To provide a meaningful evaluation of BCF, it is necessary to interpret all observations within the context of insulin resistance. Therefore, this review also discusses methods utilized to quantitate insulin-dependent glucose metabolism, such as the IVGTT and the euglycemic-hyperinsulinemic clamp procedures. In addition, an example is presented of a mathematical modeling approach that can use data from BCF measurements to develop a better understanding of BCF behavior and the overall status of glucose tolerance.
Therapeutic Manipulation of Myocardial Metabolism Honka, Henri; Solis-Herrera, Carolina; Triplitt, Curtis ...
Journal of the American College of Cardiology,
04/2021, Letnik:
77, Številka:
16
Journal Article
Recenzirano
Odprti dostop
The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 ...diabetes remain to be defined. It is likely that some of the beneficial cardiac effects of these antidiabetic drugs are mediated, in part, by altered myocardial metabolism. Common cardiometabolic disorders, including the metabolic (insulin resistance) syndrome and type 2 diabetes, are associated with altered substrate utilization and energy transduction by the myocardium, predisposing to the development of heart disease. Thus, the failing heart is characterized by a substrate shift toward glycolysis and ketone oxidation in an attempt to meet the high energetic demand of the constantly contracting heart. This review examines the metabolic pathways and clinical implications of myocardial substrate utilization in the normal heart and in cardiometabolic disorders, and discusses mechanisms by which antidiabetic drugs and metabolic interventions improve cardiac function in the failing heart.
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•Bioengineering of cardiac metabolism represents a novel strategy to improve cardiac function and slow the progression of myocardial disease.•Modification of myocardial metabolism by SGLT-2 inhibitors, GLP-1 RAs, and pioglitazone can reduce CV events in patients with type 2 diabetes.•The potential benefit of shifting fuel utilization pathways in patients with HF should be investigated in future trials.
While not traditionally discussed, the kidneys' contributions to maintaining glucose homeostasis are significant and include such functions as release of glucose into the circulation via ...gluconeogenesis, uptake of glucose from the circulation to satisfy their energy needs, and reabsorption of glucose at the level of the proximal tubule. Renal release of glucose into the circulation is the result of glycogenolysis and gluconeogenesis, respectively involving the breaking down and formation of glucose-6-phosphate from precursors (eg, lactate, glycerol, amino acids). With regard to renal reabsorption of glucose, the kidneys normally retrieve as much glucose as possible, rendering the urine virtually glucose free. The glomeruli filter from plasma approximately 180 grams of D-glucose per day, all of which is reabsorbed through glucose transporter proteins that are present in cell membranes within the proximal tubules. If the capacity of these transporters is exceeded, glucose appears in the urine. The process of renal glucose reabsorption is mediated by active (sodium-coupled glucose cotransporters) and passive (glucose transporters) transporters. In hyperglycemia, the kidneys may play an exacerbating role by reabsorbing excess glucose, ultimately contributing to chronic hyperglycemia, which in turn contributes to chronic glycemic burden and the risk of microvascular consequences. This article provides an extensive review of the kidneys' role in normal human physiology, the mechanisms by which they contribute to glucose regulation, and the potential impact of glucose imbalance on the kidneys.
Aim: To investigate the benefits of dapagliflozin DAPA on renal hemodynamics in type 2 diabetes patients T2D with glomerular hyperfiltration.
Design and Methods: 24 T2D with elevated HYPER and normal ...NORMO GFR, measured by Iohexol, randomized to either DAPA, 10mg/day DAPA/HYPER, n=6; DAPA/NORMO, n=6 or metformin+glipizide CON/HYPER, n=6; CON/NORMO, n=6 for 4 months. Hyperfiltration was defined as GFR>125ml/min/1.73m2. Renal plasma (blood) flow RP(B)F measured with PAH divided by (1-Hct), mean arterial pressure MAP, filtration fraction FF and renal vascular resistance RVR were determined before and after treatment.
Results: A1c% decreased similarly in DAPA/HYPER (8.3±0.2 vs. 6.8±0.2), CON/HYPER (8.7±0.3 vs. 7.2±0.1), DAPA/NORMO (8.6±0.3 vs. 7.3±0.2) and CON/NORMO (8.2±0.3 vs. 7.4±0.2). Body weightKg was reduced in DAPA/HYPER (89±4 vs. 84±4) and DAPA/NORMO (90±3 vs. 87±2) but not in CON/HYPER (86±4 vs. 87±3) and CON/NORMO (87±4 vs. 91±3) (p<0.05). GFR declined by 17% in DAPA/HYPER and by 8% in DAPA/NORMO (both, p<0.05) but did not change in CON. FF and RVR fell in DAPA but not in CON. Renal hemodynamics at baseline PRE-Tx and after 4 months POST-Tx are shown in the table.
Conclusion These results indicate that dapagliflozin, but not metformin+glipizide therapy, normalizes glomerular hyperfiltration and reduces renal vascular resistance in hyperfiltering type 2 diabetes patients.
Disclosure
G.Baskoy: None. Y.Qin: None. E.Cersosimo: None. C.Solis-herrera: None. J.M.Adams: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk, Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. C.L.Triplitt: Speaker's Bureau; Novo Nordisk.
Funding
AstraZeneca; Texas Diabetes Institute
Aim: To investigate the renal hemodynamic effects of SGLT-2i therapy in patients with type 2 diabetes T2D.
Design & Methods: We recruited 24 drug naïve T2D, not receiving ACEi/ARBs. GFR ...>100ml/min/1.73m2 was measured with Iohexol clearance and renal plasma (blood) flow RP(B)F with PAH clearance divided by (1-Hct). Mean arterial pressure MAP and renal vascular resistance RVR were determined before and 4 months after dapagliflozin 10mg/day (DAPA, n=12); results were compared to T2D receiving metformin±glipizide to achieve similar glycemic reduction (CONTROL, n=12).
Results: HbA1c decreased equally in DAPA (8.2±0.2 to 7.1±0.2%) and CONTROL (8.4±0.3 to 7.2±0.1%); body weight decreased in DAPA (89.9±4.0 to 86.2±4.2 kg) and rose in CONTROL (86.5±6.2 to 88.9±5.5 kg). GFR ml/min/1.73m2 declined in DAPA (118±5 to 103±5) but not in CONTROL (113±6 vs. 114±7) (p<0.01). RPF ml/min did not change in DAPA (668±65 vs. 676±70) and CONTROL (630±40 vs. 629±39), while filtration fraction FF decreased in DAPA (18±1 vs. 15±1%) but not in CONTROL (18±2 vs. 18±2%) (p<0.05). MAP mmHg declined in DAPA (95.4±2.6 vs. 89.9±2.5) but not in CONTROL (90.3±4.1 vs. 90.7±2.1) (p<0.05). Thus, calculated RVR mmHg/L/min in DAPA decreased (87.0±4.2 to 77.6±2.9), whereas it did not change (86.2±3.8 to 86.4±4.2) in CONTROL after 4 months of therapy (p<0.05).
Conclusion: Despite equal glycemic control, treatment with dapagliflozin, but not with metformin+glipizide, reduced glomerular filtration fraction and renal vascular resistance. Thus, unlike studies in T1D, our data suggest that in T2D post-glomerular vasodilatation is the predominant reno-protective mechanism of SGLT-2 inhibitors. Concomitant pre-glomerular vasoconstriction, however, cannot be excluded.
Disclosure
Y.Qin: None. G.Baskoy: None. C.L.Triplitt: Speaker's Bureau; Novo Nordisk. C.Solis-herrera: None. J.M.Adams: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk, Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. E.Cersosimo: None.
Funding
AstraZeneca; Texas Diabetes Institute
The prevalence of diabetes mellitus (DM) increased by 49% between 1990 and 2000, reaching nearly epidemic proportions. In 2010, DM (type 1 or 2) was estimated to affect nearly 30% (10.9 million) of ...people 65 years and older and 215,000 of those younger than 20 years. Macrovascular and microvascular complications can occur; DM is a major cause of heart disease and stroke, and is the seventh leading cause of death in the United States. Based on 2007 data, the economic impact of DM is considerable, with total costs, direct medical costs, and indirect costs estimated at $174 billion, $116 billion, and $58 billion, respectively. Normal glucose regulation is maintained by an intricate interaction between pancreatic β-cells (insulin/amylin), pancreatic α-cells (glucagon), and associated organs (eg, intestines, liver, skeletal muscle, adipose tissue). Newly elucidated mechanisms include the involvement of the kidneys in glucose regulation, as well as central glucose regulation by the brain. The central defects in type 2 diabetes mellitus (T2DM) are decreased insulin secretion, glucoregulatory hormone deficiency/resistance, and insulin resistance, resulting in abnormal glucose homeostasis. This article provides an extensive review of mechanisms involved in physiologic blood glucose regulation and imbalances in glucose homeostasis.
Abstract
Purpose
To provide pharmacists with information on counseling patients with type 2 diabetes (T2D) receiving oral semaglutide.
Summary
Oral semaglutide, the first oral glucagon-like peptide 1 ...(GLP-1) receptor agonist (GLP-1RA), was approved for the treatment of adults with T2D by the US Food and Drug Administration in September 2019. Semaglutide has been coformulated with the absorption enhancer sodium N-(8-2-hydroxybenzoyl amino) caprylate to improve bioavailability of semaglutide following oral administration. Oral semaglutide has been shown to have efficacy and safety profiles similar to those of other GLP-1RAs. Many patients with T2D have a complex oral medication regimen to manage their T2D and concomitant chronic comorbid conditions. Therefore, it is important that patients follow the dose administration instructions closely: oral semaglutide should be taken on an empty stomach upon waking with a sip (≤120 mL) of plain water and at least 30 minutes before the first food, beverage, or other oral medications of the day. The most common adverse effects of oral semaglutide are gastrointestinal (typically nausea, diarrhea, and vomiting). It is important for pharmacists to counsel patients prescribed oral semaglutide about optimal oral dosing, why correct dosing conditions are necessary, expected therapeutic response, and effective strategies to mitigate potential gastrointestinal adverse events.
Conclusion
Information and practical strategies provided by pharmacists may facilitate initiation and maintenance of oral semaglutide therapy and ensure that each patient achieves an optimal therapeutic response.
Aim: To examine the renal hemodynamic effects of SGLT-2i therapy in type 2 diabetes patients T2D.
Design & Methods: T2D (n=20) with normal GFR measured with 24-hour creatinine clearance ...CrCl>100ml/min/1.73m2, who were not receiving ACEi or ARB, had renal blood flow (RBF) measured using PAH clearance divided by (1-Hct) and mean arterial pressure MAP to calculate renal vascular resistance RVR prior to and 4 months after Dapagliflozin 10mg/day (DAPA, n=10) . Results were compared to T2D treated with metformin ± glipizide to achieve similar glycemic control (Control, n=10) .
Results: HbA1c decreased equally in DAPA (8.6±0.5% to 7.4±0.3%) and CONTROL (8.7±0.3 to 7.5±0.2%) . There was a non-significant increase in RBF (ml/min) in DAPA compared to Control. MAP (mmHg) decreased by 8.5% from 98.4±2.9 mmHg to 90.0±2.0 mmHg and RVR by 21.4% from 87.9±5.1 mmHg/l/min to 69.1±5.2 mmHg/l/min in the DAPA group, while MAP & RVR remained unchanged in CONTROL group. Data at baseline Pre-Rx and after 4 months of therapy Post-Rx are shown in the table.
Conclusion: These findings show that, with equivalent glycemic control, dapagliflozin, but not metformin/glipizide, is accompanied by a decrease in renal vascular resistance, without significant change in RBF. Unlike studies in T1D, our results suggest that in T2D patients post-glomerular vasodilatation is the primary reno-protective mechanism of SGLT-2i therapy.
Disclosure
M.Barkhordarian: None. C.L.Triplitt: Consultant; Bayer AG, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. C.Solis-herrera: Speaker's Bureau; Novo Nordisk. J.M.Adams: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. E.Cersosimo: Research Support; AstraZeneca.
Funding
AstraZeneca
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