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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. [ABSTRACT FROM AUTHOR]

The article announces the retirement of Lyn Reynolds as director of the American Diabetes Association's (ADA) editorial department.

Background: SGLT2 inhibition causes a "paradoxical" increase in EGP, indicating the presence of a "reno-hepatic axis." Aim: We measured EGP after SGLT2 inhibition in renal transplant subjects with and without type 2 diabetes to evaluate the role of renal nerves and SNS in mediating this "reno-hepatic axis." Six T2D (A1c = 7.2±0.1) and 8 non-T2D (A1c = 5.6±0.1) with normal renal function and no history of rejection (prednisone ≤ 5mg/day) received two 6-hr measurements of EGP preceded by dapagliflozin or placebo. Results: Following DAPA in T2D, FPG (143±15 to 112±9 mg/dl, p=0.01) and FPI (14±3 to 11±2, p=0.02) decreased while glucagon increased (45±13 to 54±14 pg/mL, p=0.09) (all p<0.05 vs. placebo); plasma epinephrine and norepi did not change from baseline. Following placebo, EGP decreased (p<0.01) in both T2D and non-DM. In contrast, after DAPA EGP increased (p<0.01) in both T2D (by 0.4±0.1 mg/kg.min) and in non-T2D (by 0.1±0.1 mg/kg.min) compared to placebo. The DAPA-induced increment in EGP production was highly correlated (r = 0.824, p<0.001) with the increment in urinary glucose excretion in all subjects (Figure). Conclusions: (1) Renal denervation in renal transplant patients failed to block the DAPA-mediated stimulation of EGP; (2) DAPA-stimulated rise in EGP is strongly related to the increase in urinary glucose excretion blunting the decline in FPG. Disclosure: C. Solis-Herrera: Advisory Panel; Self; Sanofi. M. Alatrach: None. C. Agyin: None. H. Honka: None. R. Patel: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. J.M. Adams: None. A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. M. Abdul-Ghani: None. E. Cersosimo: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. [ABSTRACT FROM AUTHOR]

Elevated SNSA induces dysglycemia by enhancing adipose lipolysis and stimulating hepatic glucose production. It also promotes cardiovascular disease (CVD) by multiple mechanisms including augmenting systemic and vascular reactive oxygen and nitrogen species (ROS, RNS) generation. Elevated plasma prolactin (subclinical hyperprolactinemia) has also been associated with systemic inflammation, which can potentiate dysglycemia and CVD. BQR, the only dopamine agonist approved for treatment of T2D, improves postprandial dysglycemia and reduces CVD events. To evaluate mechanisms for the glucose lowering and CVD protective effects of BQR, we evaluated BQR's effect on plasma markers of SNSA and ROS/RNS and plasma prolactin and leptin from a mechanistic study in which BQR added to 15 T2D subjects (HbA1c 8.3%) treated with a GLP-1 RA significantly improved HbA1c (-0.6%), postprandial hyperglycemia (by 22%) and endothelial dysfunction (by 36%). Plasma norepinephrine (NE), normetanephrine (NM), TBAR (a marker of systemic OS), nitrotyrosine (NT, a marker of systemic oxidative/nitrosative stress), prolactin and leptin were measured at baseline and after 4 months of BQR add-on therapy (3.2 mg/day). Plasma NE, NM, TBAR, NT and prolactin levels were elevated at baseline and decreased significantly with BQR [NE by 33% (2.95 to 1.95 ng/mL, p <0.0005); NM by 22% (56.5 to 44.3 pg/ml, p<0.018); TBAR by 10% (10.2 to 9.2 μM, p=0.04); NT by 13% (214 to 187 nM, p<0.02); prolactin by 42% (13.0 to 7.6 ng/ml, p<0.012)]. Plasma leptin, unchanged in the whole group, decreased 23% (35.7 to 27.5 ng/mL, p=0.038) in subjects with elevated leptin (>20 ng/dl, N=7) at baseline. Conclusion: Bromocriptine-QR is the only T2D therapy known to simultaneously reduce elevated plasma NE, NM, prolactin and OS and such actions may be important for the drug's glucose lowering and CVD protective effects. Disclosure: B. Chamarthi: Employee; Self; VeroScience LLC. E. Cersosimo: None. J.M. Adams: None. M. Alatrach: None. C. Agyin: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. M. Ezrokhi: Employee; Self; VeroScience LLC. S. Luo: Employee; Self; VeroScience LLC. E. Duvallet: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. [ABSTRACT FROM AUTHOR]

Aim: To examine the role of plasma glucose (GLU), insulin (INS) and glucagon (GG) changes in EGP stimulation during glucosuria (UGE) following SGLT2i administration. Methods: Using tracer (3-3H-glucose), 30 T2D patients (Age=55±1y, BMI=32.2±0.7kg/m2, FPG=140±6mg/dl, A1c=7.3±0.1%) received three 300-min procedures at 2-weeks intervals: (I) control clamp (CON) with no glucose/hormone infusions; (II) pancreatic clamp (PAN) with somatostatin (0.75mg/h), basal replacement of insulin (0.1mU/kg.min) and glucagon (0.3ng/kg.min); (III) isoglycemic clamp (ISO) with variable dextrose infusion to maintain GLU equal to baseline. Prior to start of each clamp subjects received placebo (PCB, n=10) or dapagliflozin 10mg (DAPA, n=20). Results: After DAPA (CON), INS decreased (-7±1µU/ml) while GG increased (+10±1pg/ml) (both p<0.05 vs. PCB). Despite UGE of 0.48mg/kg.min, GLU decline was modest (-31±1) due to a "paradoxical" rise in EGP after DAPA. During PAN with DAPA and PCB, INS and GG were unchanged from baseline, and EGP stimulation in DAPA compared to PCB still increased, yet GLU decline was modest (-28.4±3.0). During ISO, EGP decreased markedly with DAPA as well as PCB despite similar plasma GG and INS concentrations. Conclusion: DAPA-induced glucosuria stimulation of EGP cannot be entirely explained by the rise in plasma glucagon or decline in plasma insulin. Disclosure: M. Alatrach: None. C. Agyin: None. N. Laichuthai: None. J.M. Adams: None. M. Abdul-Ghani: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None. [ABSTRACT FROM AUTHOR]

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.

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.

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.

Although there are numerous effective pharmacotherapeutic agents available to treat type 2 diabetes, 5% to 10% of the population with diabetes experience secondary failure. To help combat this issue, it is imperative that clinicians understand the limitations of some current therapies. Secondary failure can be due to decreasing beta cell function, poor adherence to treatment, weight gain, reduction of exercise, changes in diet, or illness. Glycemic control and cardiovascular risk reduction are of paramount concern; however, the nonglycemic effects of several new therapies to treat diabetes may be advantageous and positively affect the long-term cost of therapy. The discoveries of amylin and glucagonlike peptide-1 have furthered our understanding of the abnormalities involved in diabetes, enabling the development of additional therapeutic options. Incretin-based therapy, including incretin mimetics such as exenatide and the yet-to-be-approved dipeptidyl peptidase-4 inhibitors, and new basal and inhaled insulin may change the way we currently treat type 2 diabetes.