Lowering plasma glucose concentration by inhibiting renal sodium–glucose cotransport

Maintaining normoglycaemia not only reduces the risk of diabetic microvascular complications but also corrects the metabolic abnormalities that contribute to the development and progression of hyperglycaemia, that is insulin resistance and beta‐cell dysfunction. Progressive beta‐cell failure, in addition to side effects associated with many current antidiabetic agents, for example hypoglycaemia and weight gain, presents major obstacles to the achievement of the recommended goal of glycaemic control in patients with type 2 diabetes mellitus (T2DM). Thus, novel effective therapies are needed for optimal glucose control in subjects with T2DM. Most recently, specific inhibitors of the renal sodium–glucose cotransporter 2 (SGLT2) have been developed to produce glucosuria and lower the plasma glucose concentration. Because of the iR unique mechanism of action, which is independent of insulin secretion and insulin action, these agents are effective in lowering the plasma glucose concentration in all stages of the disease and can be combined with all other antidiabetic agents. In this review, we will summarize the available data concerning the mechanism of action, efficacy and safety of this novel class of antidiabetic agents.     

Oral glucose tolerance test‐based calculation identifies different glucose intolerance phenotypes within the impaired fasting glucose range

Aims/Introduction

The conventional oral glucose tolerance test (OGTT) cannot detect future diabetics among isolated impaired fasting glucose (is‐IFG) nor normal glucose tolerant (NGT) groups. By analyzing the relationship between fasting (FPG) and 2‐h plasma glucose (2hPG), the present study identifies is‐IFG subjects liable to worsening glucose homeostasis.

Materials and Methods

Oral glucose tolerance test was carried out in 619 patients suffering from obesity, hypertension or dyslipidemia, whose FPG was in the 100–125 mg/dL range. We calculated the percentage increment of 2hPG with respect to FPG (PG%) in these patients using the formula: ([2hPG − FPG] / FPG) × 100. Differences in β‐cell function within is‐IFG patients were assessed by estimated insulin sensitivity index (EISI), first‐phase insulin release (1stPH) and 1stPH/1/EISI (1stPH_corrected).

Results

Diabetes was diagnosed in 69 patients (11.2%), combined IFG/impaired glucose tolerance (IGT) in 185 patients (29.9%) and is‐IFG in 365 patients (58.9%). Is‐IFG was subdivided into PG% tertile groups: the percentage of females increased from 25% in the lowest to 45.2% in the highest tertile (χ² = 18.7, P < 0.001). Moving from the lowest to the highest PG% tertile group, insulin and 2hPG concentrations rose, whereas FPG, EISI, and 1stPH_corrected decreased progressively and significantly. Furthemore, PG% correlated inversely with EISI (r = −0.44, P < 0.0001) and 1stPH_corrected (r = −0.38, P < 0.0001).

Conclusions

Oral glucose tolerance test does differentiate the great heterogeneity in metabolic disorders of patients with FPG 100–125 mg/dL. Furthermore, PG% can expand the diagnostic power of OGTT in the is‐IFG range by distinguishing metabolic phenotypes very likely to herald different clinical risks.     

Renal threshold for glucose reabsorption predicts diabetes improvement by sodium‐glucose cotransporter 2 inhibitor therapy

In the present study we examined the efficacy of sodium‐glucose cotransporter 2 inhibitors on improvement of glycated hemoglobin (HbA1c) in comparison with the renal threshold for glucose reabsorption in patients with type 2 diabetes mellitus. Patients visited the hospital once a month for a regular follow‐up examination with the determination of blood glucose and HbA1c levels, and urinary glucose concentration from spot urine samples. Patient samples were compared before and after ipragliflozin administration. We defined the renal threshold for glucose reabsorption as the lowest blood glucose level that correlated with the first detectable appearance of urine glucose. These data showed a significant negative correlation between improvement of HbA1c level and renal threshold for glucose reabsorption in patients treated with the sodium‐glucose cotransporter 2 inhibitor. These findings show that patients who have a higher renal threshold for glucose reabsorption can be expected to more effectively respond to sodium‐glucose cotransporter 2 inhibitor therapy in terms of lowering HbA1c levels.     

Attempt to improve glucose control in type 2 diabetic patients by education about real-time glucose monitoring

The effectiveness of a specific educational programme involving the use of a real-time glucose-sensor system (Guardian RT^®) to improve glucose control was investigated in patients with poorly controlled type 2 diabetes despite insulin therapy. Ten patients participated in a randomized crossover study comparing two 3-month periods, during which glucose levels were monitored by either self-monitoring of blood glucose (SMBG) alone or by Guardian RT^® (restricted to 1 week per month) in addition to SMBG. Only four of the enrolled patients completed both periods, while dropouts were mainly due to technical difficulties in using the device. All six patients who completed the first 3-month period showed a reduction in glycated haemoglobin (HbA_1c) level whatever the mode of glucose monitoring (study effect). A further reduction in HbA_1c level was observed in two of the three patients using the Guardian RT^® during the second period. Less frequent symptomatic hypoglycaemic episodes were noted during the 3-month period with the device in the four patients who completed both study periods. These limited, but promising, results of this pilot study appear to justify the initiation of a larger study to assess the use of a real-time glucose sensor in carefully selected patients with type 2 diabetes.     

Exercise lowers postprandial glucose but not fasting glucose in type 2 diabetes: a meta‐analysis of studies using continuous glucose monitoring

Exercise has repeatedly been shown to improve glycemic control as assessed by glycated hemoglobin. However, changes in glycated hemoglobin do not provide information regarding which aspects of glycemic control have been altered. The purpose of this systematic review was to examine the effect of exercise as assessed by continuous glucose monitoring systems (CGMS) in type 2 diabetes. Databases (PubMed, Medline, EMBASE) were searched up to February 2013. Eligible studies had participants with type 2 diabetes complete standardized exercise protocols and used CGMS to measure changes in glycemic control. Randomized controlled trials, crossover trials and studies with pre‐post designs were included. Average glucose concentration, daily time spent in hyperglycemia or hypoglycemia, and fasting glucose concentration were compared between exercise and control conditions. Eleven studies met the inclusion criteria and were included in the review. Eight studies had short‐term (≤2 weeks) exercise interventions, whereas three studies had a longer‐term intervention (all >2 months). The types of exercises utilized included aerobic, resistance and a combination of the two. The eight short‐term studies were included in quantitative analysis. Exercise significantly decreased average glucose concentrations (‐0.8 mmol/L, p < 0.01) and daily time spent in hyperglycemia (‐129 minutes, p < 0.01), but did not significantly affect daily time spent in hypoglycemia (‐3 minutes, p = 0.47) or fasting glucose (‐0.3 mmol/L, p = 0.13). The four randomized crossover trials had similar findings compared to studies with pre‐post designs. Exercise consistently reduced average glucose concentrations and time spent in hyperglycemia despite not significantly affecting outcomes such as fasting glucose and hypoglycemia. Copyright © 2013 John Wiley & Sons, Ltd.     

Outcome of glucose tolerance condition in patients with normal glucose tolerance with either persistently high or low 1-h postchallenge glucose levels in 75 g oral glucose tolerance test

International Journal of Diabetes in Developing Countries - This study aimed to investigate whether persistently high 1-h postchallenge glucose (PG) levels in a 75&nbsp;g oral glucose tolerance...     

Effects of a sodium glucose co‐transporter 2 selective inhibitor,ipragliflozin, on the diurnal profile of plasma glucose in patients with type 2 diabetes: A study using continuous glucose monitoring

Aims/Introduction

To assess the effects of sodium glucose co-transporter 2 inhibitor therapy on the pathophysiology of type 2 diabetes.

Materials and Methods

We administered ipragliflozin to 21 inpatients with type 2 diabetes for 7 days, and analyzed the diurnal profiles of plasma glucose and 3-hydroxybutyrate. A total of 21 age-, sex- and body mass index-matched diabetic patients served as controls.

Results

Continuous glucose monitoring showed that the 24-h glucose curve was shifted downward without hypoglycemia by the administration of ipragliflozin. The average glucose level was reduced from 182 ± 54 mg/dL to 141 ± 33 mg/dL (P < 0.0001). The magnitude of the reduction was highly correlated with the baseline average glucose level. Homeostasis model assessment of insulin resistance was decreased, and homeostasis model assessment of β-cell function was increased during the treatment. Urinary glucose excretion was correlated with the average glucose level both on day 0 and on day 7, although the regression line was steeper and shifted leftward on day 7. The ipragliflozin-treated patients lost more weight than the control patients (1.4 ± 0.5 vs 0.5 ± 0.6 kg, P < 0.0001). Plasma levels of 3-hydroxybutyrate were significantly increased with peaks before breakfast and before dinner. Patient age and bodyweight loss were negatively and positively correlated with the peak levels of 3-hydroxybutyrate on day 7, respectively.

Conclusions

The ipragliflozin treatment improved the 24-h glucose curve without causing hypoglycemia. The close correlation between the magnitude of glucose reduction and the baseline plasma glucose concentration suggests that the risk of hypoglycemia is likely low. It might be prudent to monitor ketone body levels in younger patients and in patients with rapid weight loss.