Renal glucose metabolism in normal physiological conditions and in diabetes.

The kidney plays an important role in glucose homeostasis via gluconeogenesis, glucose utilization, and glucose reabsorption from the renal glomerular filtrate. After an overnight fast, 20-25% of glucose released into the circulation originates from the kidneys through gluconeogenesis. In this post-absorptive state, the kidneys utilize about 10% of all glucose utilized by the body. After glucose ingestion, renal gluconeogenesis increases and accounts for approximately 60% of endogenous glucose release in the postprandial period. Each day, the kidneys filter approximately 180g of glucose and virtually all of this is reabsorbed into the circulation. Hormones (most importantly insulin and catecholamines), substrates, enzymes, and glucose transporters are some of the various factors influencing the kidney's role. Patients with type 2 diabetes have an increased renal glucose uptake and release in the fasting and the post-prandial states. Additionally, glucosuria in these patients does not occur at plasma glucose levels that would normally produce glucosuria in healthy individuals. The major abnormality of renal glucose metabolism in type 1 diabetes appears to be impaired renal glucose release during hypoglycemia.

Hypoglycemia in Patients with Diabetes and Renal Disease.

This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetic kidney disease and reviews therapeutic limitations in this situation.

Hypoglycemia, chronic kidney disease, and diabetes mellitus.

Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched for literature published in English from January 1989 to May 2014 for diabetes mellitus, hypoglycemia, chronic kidney disease, and chronic renal insufficiency.

SGLT2 inhibitors in the treatment of type 2 diabetes.

The kidney plays an important role in glucose homeostasis via its production, utilization, and, most importantly, reabsorption of glucose from glomerular filtrate which is largely mediated via the sodium glucose co-transporter 2 (SGLT2). Pharmacological inhibition of SGLT2 increases urinary glucose excretion and decreases plasma glucose levels in an insulin-independent manner. Agents that inhibit SGLT2 represent a novel class of drugs, which has recently become available for treatment of type 2 diabetes. This article summarizes the rationale for use of these agents and reviews available clinical data on their efficacy, safety, and risks/benefits.

Hypoglycemia.

Hypoglycemia remains a common problem for patients with diabetes and is associated with substantial morbidity and mortality. This article summarizes our current knowledge of the epidemiology, pathogenesis, risk factors, and complications of hypoglycemia in patients with diabetes and discusses prevention and treatment strategies.

Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X).

OBJECTIVE: To compare efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS: Adults with diabetes inadequately controlled (HbA1c 7-10%) with metformin were randomized to lixisenatide 20 µg once daily (n=318) or exenatide 10 µg twice daily (n=316) in a 24-week (main period), open-label, parallel-group, multicenter study. The primary objective was a noninferiority assessment of lixisenatide versus exenatide in HbA1c change from baseline to week 24. RESULTS: Lixisenatide once daily demonstrated noninferiority in HbA1c reduction versus exenatide twice daily. The least squares mean change was -0.79% (mean decrease 7.97 to 7.17%) for lixisenatide versus -0.96% (mean decrease 7.96 to 7.01%) for exenatide, and treatment difference was 0.17% (95% CI, 0.033-0.297), meeting a predefined noninferiority upper CI margin of 0.4%. Responder rate (HbA1c<7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P<0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P<0.05). CONCLUSIONS: Add-on lixisenatide once daily in type 2 diabetes inadequately controlled with metformin demonstrated noninferior improvements in HbA1c, with slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability compared with exenatide twice daily.

Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono).

OBJECTIVE: To assess efficacy and safety of lixisenatide monotherapy in type 2 diabetes. RESEARCH DESIGN AND METHODS: Randomized, double-blind, 12-week study of 361 patients not on glucose-lowering therapy (HbA(1c) 7-10%) allocated to one of four once-daily subcutaneous dose increase regimens: lixisenatide 2-step (10 µg for 1 week, 15 µg for 1 week, and then 20 µg; n = 120), lixisenatide 1-step (10 µg for 2 weeks and then 20 µg; n = 119), placebo 2-step (n = 61), or placebo 1-step (n = 61) (placebo groups were combined for analyses). Primary end point was HbA(1c) change from baseline to week 12. RESULTS: Once-daily lixisenatide significantly improved HbA(1c) (mean baseline 8.0%) in both groups (least squares mean change vs. placebo: -0.54% for 2-step, -0.66% for 1-step; P < 0.0001). Significantly more lixisenatide patients achieved HbA(1c) <7.0% (52.2% 2-step, 46.5% 1-step) and ≤ 6.5% (31.9% 2-step, 25.4% 1-step) versus placebo (26.8% and 12.5%, respectively; P < 0.01). Lixisenatide led to marked significant improvements of 2-h postprandial glucose levels and blood glucose excursions measured during a standardized breakfast test. A significant decrease in fasting plasma glucose was observed in both lixisenatide groups versus placebo. Mean decreases in body weight (∼2 kg) were observed in all groups. The most common adverse events were gastrointestinal-nausea was the most frequent (lixisenatide 23% overall, placebo 4.1%). Symptomatic hypoglycemia occurred in 1.7% of lixisenatide and 1.6% of placebo patients, with no severe episodes. Safety/tolerability was similar for the two dose regimens. CONCLUSIONS: Once-daily lixisenatide monotherapy significantly improved glycemic control with a pronounced postprandial effect (75% reduction in glucose excursion) and was safe and well tolerated in type 2 diabetes.

Development of the sodium-glucose co-transporter 2 inhibitor dapagliflozin for the treatment of patients with type 2 diabetes mellitus.

Dapagliflozin is a highly selective sodium-glucose co-transporter 2 inhibitor developed for the treatment of Type 2 diabetes mellitus. Its inhibition of sodium-glucose co-transporter 2 blocks glucose reabsorption in the proximal tubule of the kidney, increasing renal glucose excretion via the urine, resulting in reduction of glycated hemoglobin, fasting plasma glucose and postprandial plasma glucose in patients with Type 2 diabetes mellitus. The pharmacokinetics and pharmacodynamics of dapagliflozin are suitable for once-daily dosing. Dapagliflozin improves glycemic control when used as monotherapy and when used in combination with other antidiabetic treatments. Throughout all phases of clinical studies, dapagliflozin was generally well tolerated. Increased events suggestive of urinary tract and genital infections have been reported; most resolved with conventional treatment. Unexpected numerical imbalances between dapagliflozin and comparator were noted for breast and bladder cancers. The potential for increased cancer risk with dapagliflozin needs to be further assessed.

Type 2 diabetes: postprandial hyperglycemia and increased cardiovascular risk.

Hyperglycemia is a major risk factor for both the microvascular and macrovascular complications in patients with type 2 diabetes. This review summarizes the cardiovascular results of large outcomes trials in diabetes and presents new evidence on the role of hyperglycemia, with particular emphasis on postprandial hyperglycemia, in adverse cardiovascular outcomes in patients with type 2 diabetes. Treatment options, including the new dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 mimetics that primarily target postprandial hyperglycemia, are also discussed. Hyperglycemia increases cardiovascular mortality, and reducing hyperglycemia lowers cardiovascular risk parameters. Control of both fasting and postprandial hyperglycemia is necessary to achieve optimal glycated hemoglobin control. Therefore, anti-hyperglycemic agents that preferentially target postprandial hyperglycemia, along with those that preferentially target fasting hyperglycemia, are strongly suggested to optimize individual diabetes treatment strategies and reduce complications.

Diabetes mellitus and gastric emptying: questions and issues in clinical practice.

It is long known that both type 1 and type 2 diabetes can be associated with changes in gastric emptying; a number of publications have linked diabetes to delayed gastric emptying of variable severity and often with poor relationship to gastrointestinal symptomatology. In contrast, more recent studies have reported accelerated gastric emptying when adjusted for glucose concentration in patients with diabetes, indicating a reciprocal relationship between gastric emptying and ambient glucose concentrations. This review proposes that gastroparesis or gastroparesis diabeticorum, a severe condition characterized by a significant impairment of gastric emptying accompanied by severe nausea, vomiting, and malnutrition, is often overdiagnosed and not well contrasted with delays in gastric emptying. The article offers a clinically relevant definition of gastroparesis that should help differentiate this rare condition from (often asymptomatic) delays in gastric emptying. The fact that delayed gastric emptying can also be observed in non-diabetic individuals under experimental conditions in which hyperglycaemia is artificially induced suggests that a delay in gastric emptying rate when blood glucose concentrations are high is actually an appropriate physiological response to hyperglycaemia, slowing further increases in blood glucose. The article discusses the strengths and weaknesses of various methodologies for assessing gastric emptying, especially with respect to the diabetes population, and reviews newer diabetes therapies that decelerate the rate of gastric emptying. These therapies may be a beneficial tool in managing postprandial hyperglycaemia because they attenuate rapid surges in glucose concentrations by slowing the delivery of meal-derived glucose.