Carolina Solis-Herrera

Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production.

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

Assessment of Pancreatic β-Cell Function: Review of Methods and Clinical Applications

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.

Mechanisms of glucose lowering of dipeptidyl peptidase-4 inhibitor sitagliptin when used alone or with metformin in type 2 diabetes: a double-tracer study.

OBJECTIVE To assess glucose-lowering mechanisms of sitagliptin (S), metformin (M), and the two combined (M+S). RESEARCH DESIGN AND METHODS We randomized 16 patients with type 2 diabetes mellitus (T2DM) to four 6-week treatments with placebo (P), M, S, and M+S. After each period, subjects received a 6-h meal tolerance test (MTT) with [14C]glucose to calculate glucose kinetics. Fasting plasma glucose (FPG), fasting plasma insulin, C-peptide (insulin secretory rate [ISR]), fasting plasma glucagon, and bioactive glucagon-like peptide (GLP-1) and gastrointestinal insulinotropic peptide (GIP) were measured. RESULTS FPG decreased from P, 160 ± 4 to M, 150 ± 4; S, 154 ± 4; and M+S, 125 ± 3 mg/dL. Mean post-MTT plasma glucose decreased from P, 207 ± 5 to M, 191 ± 4; S, 195 ± 4; and M+S, 161 ± 3 mg/dL (P < 0.01). The increase in mean post-MTT plasma insulin and in ISR was similar in P, M, and S and slightly greater in M+S. Fasting plasma glucagon was equal (∼65–75 pg/mL) with all treatments, but there was a significant drop during the initial 120 min with S 24% and M+S 34% (both P < 0.05) vs. P 17% and M 16%. Fasting and mean post-MTT plasma bioactive GLP-1 were higher (P < 0.01) after S and M+S vs. M and P. Basal endogenous glucose production (EGP) fell from P 2.0 ± 0.1 to S 1.8 ± 0.1 mg/kg ⋅ min, M 1.8 ± 0.2 mg/kg ⋅ min (both P < 0.05 vs. P), and M+S 1.5 ± 0.1 mg/kg ⋅ min (P < 0.01 vs. P). Although the EGP slope of decline was faster in M and M+S vs. S, all had comparable greater post-MTT EGP inhibition vs. P (P < 0.05). CONCLUSIONS M+S combined produce additive effects to 1) reduce FPG and postmeal plasma glucose, 2) augment GLP-1 secretion and β-cell function, 3) decrease plasma glucagon, and 4) inhibit fasting and postmeal EGP compared with M or S monotherapy.

Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes

OBJECTIVE Insulin resistance is associated with mitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium–glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production. RESEARCH DESIGN AND METHODS The study randomized 18 individuals with T2DM to dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies. RESULTS Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg ⋅ min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg ⋅ min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration. CONCLUSIONS Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.

Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males

AIM To investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals. METHODS Fourteen male T2DM patients received an oral glucose tolerance test and euglycemic hyperinsulinemic clamp at baseline and were treated for 3 weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The oral glucose tolerance test and insulin clamp were repeated at the end of weeks 2 and 3. RESULTS Dapagliflozin caused glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dL; P < .01), whereas the fasting plasma FFA concentration was unaffected. Acipimox caused a further decrease in the fasting plasma glucose concentration (by 20 mg/dL; P < .01) and a significant decrease in the fasting plasma FFA concentration. Compared to baseline, insulin-mediated glucose disposal increased significantly at week 2 (from 4.48 ± 0.50 to 5.30 ± 0.50 mg/kg · min; P < .05). However, insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline, and it increased further and significantly at week 3 compared to week 2. CONCLUSION Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and β-cell function, whereas lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves β-cell function without significantly affecting insulin sensitivity.

GLP-1 Receptor Agonists Practical Considerations for Clinical Practice

Purpose Type 2 diabetes (T2D) imparts an increased risk of adverse health outcomes in patients unable to achieve glycemic control. Patient education and individualization of treatment are important for effective management of T2D. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of injectable glucose-lowering agents that lower A1C with added benefits of weight loss and improved cardiovascular risk markers. This review discusses the role of GLP-1RAs currently approved in the United States (exenatide, liraglutide, albiglutide, dulaglutide) for T2D management and characterizes the efficacy and safety profiles of individual GLP-1RAs. Conclusions GLP-1RAs are recommended as a preferred add-on agent to existing metformin monotherapy, as first-line therapy if metformin is contraindicated or poorly tolerated, and for use in combination with other oral glucose-lowering agents or basal insulin. Shorter-acting GLP-1RAs (exenatide and liraglutide) offer improved coverage of postprandial hyperglycemia, while longer-acting GLP-1RA formulations (exenatide extended-release, dulaglutide, and albiglutide) further improve fasting plasma glucose, which can result in additional A1C lowering. Reductions in body weight and blood pressure appear similar among individual agents, and small increases in heart rate are of unknown clinical relevance. Gastrointestinal adverse events abate over time with continued treatment and are less frequent with longer-acting GLP-1RAs. Hypoglycemia incidence is low but increased when GLP-1RAs are used with insulin secretagogues or insulin. GLP-1RAs target multiple pathophysiologic mechanisms in patients with T2D and improve glycemic control, although there are some differences within this drug class that may be relevant in clinical practice. Therefore, selection of the most appropriate treatment for individual patients is important.

Empagliflozin and linagliptin combination therapy for treatment of patients with type 2 diabetes mellitus

Introduction: Many patients with type 2 diabetes mellitus (T2DM) fail to achieve the desired A1c goal because the antidiabetic medications used do not correct the underlying pathophysiologic abnormalities and monotherapy is not sufficiently potent to reduce the A1c to the 6.5 – 7.0% range. Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in T2DM. We examine combination therapy with linagliptin plus empagliflozin as a therapeutic approach for the treatment of inadequately controlled T2DM patients. Areas covered: A literature search of all human diabetes, metabolism and general medicine journals from year 2000 to the present was conducted. Glucagon like peptide-1 (GLP-1) deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. DPP-4 inhibitors (DPP4i) improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Linagliptin, a DPP-4 inhibitor, reduces HbA1c, is weight neutral, has an excellent safety profile and a low risk of hypoglycemia. The expression of sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubule is upregulated in T2DM, causing excess reabsorption of filtered glucose. The SGLT2 inhibitor (SGLT2i), empagliflozin, improves HbA1c by causing glucosuria and ameliorating glucotoxicity. It also decreases weight and blood pressure, and has a low risk of hypoglycemia. Expert opinion: The once daily oral combination of linagliptin plus empagliflozin does not increase the risk of hypoglycemia and tolerability and discontinuation rates are similar to those with each as monotherapy. At HbA1c values below 8.5% linagliptin/empagliflozin treatment produces an additive effect, whereas above 8.5%, there is a less than additive reduction with combination therapy compared with the effect of each agent alone. Linagliptin/empagliflozin addition is a logical combination in patients with T2DM, especially those with an HbA1c < 8.5%.

Nephropathy in youth and young adults with type 2 diabetes.

The occurrence and progression of nephropathy associated with early onset type 2 diabetes (T2D) is a consequence of the ongoing epidemic of childhood obesity. Minimal evidence regarding treatment effectiveness of renovascular comorbidities in youth with early onset T2D is available, due to the relatively recent emergence of T2D in youth and young adults. Extrapolation of adult therapy guidelines is not an ideal approach to making therapeutic decisions in this population. Evolving management and intervention strategies are based on accumulating longitudinal data from cohorts of well characterized youth and young adults with T2D. The degree of similarity in histologic findings and disease specific characteristics of kidney disease in patients with early onset T2D and albuminuria compared with affected adults is not well characterized. Early aggressive therapies to minimize the impact of nephropathy are indicated as the evidence for best therapies in youth with T2D are further explored.

Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes

OBJECTIVE To examine the effect of pioglitazone on myocardial insulin sensitivity and left ventricular (LV) function in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Twelve subjects with T2D and 12 with normal glucose tolerance received a euglycemic insulin clamp. Myocardial glucose uptake (MGU) and myocardial perfusion were measured with [18F]fluoro-2-deoxy-d-glucose and [15O]H2O positron emission tomography before and after 24 weeks of pioglitazone treatment. Myocardial function and transmitral early diastolic relation/atrial contraction (E/A) flow ratio were measured with magnetic resonance imaging. RESULTS Pioglitazone reduced HbA1c by 0.9%; decreased systolic and diastolic blood pressure by 7 ± 2 and 7 ± 2 mmHg, respectively (P < 0.05); and increased whole-body insulin-stimulated glucose uptake by 71% (3.4 ± 1.3 to 5.8 ± 2.1 mg/kg · min; P < 0.01) in subjects with T2D. Pioglitazone enhanced MGU by 75% (0.24 ± 0.14 to 0.42 ± 0.13 μmol/min · g; P < 0.01) and myocardial perfusion by 16% (0.95 ± 0.16 to 1.10 ± 0.25 mL/min · g; P < 0.05). Measures of diastolic function, E/A ratio (1.04 ± 0.3 to 1.25 ± 0.4) and peak LV filling rate (349 ± 107 to 433 ± 99 mL/min), both increased (P < 0.01). End-systolic volume, end-diastolic volume, peak LV ejection rate, and cardiac output trended to increase (P not significant), whereas the ejection fraction (61 ± 6 to 66 ± 7%) and stroke volume increased significantly (71 ± 20 to 80 ± 20 L/min; both P < 0.05). CONCLUSIONS Pioglitazone improves whole-body and myocardial insulin sensitivity, LV diastolic function, and systolic function in T2D. Improved myocardial insulin sensitivity and diastolic function are strongly correlated.

Empagliflozin Treatment Is Associated With Improved β-Cell Function in Type 2 Diabetes Mellitus

Abstract Objective To examine whether lowering plasma glucose concentration with the sodium-glucose transporter-2 inhibitor empagliflozin improves β-cell function in patients with type 2 diabetes mellitus (T2DM). Methods Patients with T2DM (N = 15) received empagliflozin (25 mg/d) for 2 weeks. β-Cell function was measured with a nine-step hyperglycemic clamp (each step, 40 mg/dL) before and at 48 hours and at 14 days after initiating empagliflozin. Results Glucosuria was recorded on days 1 and 14 [mean ± standard error of the mean (SEM), 101 ± 10 g and 117 ± 11 g, respectively] after initiating empagliflozin, as were reductions in fasting plasma glucose levels (25 ± 6 mg/dL and 38 ± 8 mg/dL, respectively; both P < 0.05). After initiating empagliflozin and during the stepped hyperglycemic clamp, the incremental area under the plasma C-peptide concentration curve increased by 48% ± 12% at 48 hours and 61% ± 10% at 14 days (both P < 0.01); glucose infusion rate increased by 15% on day 3 and 16% on day 14, compared with baseline (both P < 0.05); and β-cell function, measured with the insulin secretion/insulin resistance index, increased by 73% ± 21% at 48 hours and 112% ± 20% at 14 days (both P < 0.01). β-cell glucose sensitivity during the hyperglycemic clamp was enhanced by 42% at 14 hours and 54% at 14 days after initiating empagliflozin (both P < 0.01). Conclusion Lowering the plasma glucose concentration with empagliflozin in patients with T2DM augmented β-cell glucose sensitivity and improved β-cell function.