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.In diet-treated patients with type 2 diabetes mellitus (T2DM) and HbA_1c of ∼8.0%, sitagliptin (S) reduces HbA_1c by 0.6–0.7% over a 6-month period (1). A slightly greater HbA_1c decline (∼0.8–0.9%) is observed when metformin (M) therapy is added to S (2). Dipeptidyl peptidase (DPP)-4 inhibitors predominantly affect the postprandial plasma glucose excursion, but a significant, albeit modest, reduction in fasting plasma glucose (FPG) also is observed (1–3). The mechanism of action of the DPP-4 inhibitors has been well studied and includes increased plasma glucagon-like peptide (GLP)-1 and gastrointestinal insulinotropic peptide (GIP) levels, resulting in increased insulin and reduced glucagon secretion (4–6). The increase in plasma insulin and the decline in glucagon inhibit basal endogenous glucose production (EGP) and enhance the suppression of EGP without affecting splanchnic (hepatic) glucose uptake or gastric emptying (6,7). Therapy with S and M combined (M+S) exerts an additive effect to reduce HgA_1c; the mechanism of action of this combination has yet to be examined. Several studies have demonstrated that M inhibits DPP-4 activity, thus increasing plasma active GLP-1 levels (8–10). There are also reports indicating that the decline in plasma glucose with M therapy can restore the β-cells’ sensitivity to the stimulatory effect of incretins on insulin secretion (11,12). Despite these reports, we still do not fully understand the reasons why the use of M in diabetic patients is not accompanied by changes in insulin release. In the current study, we used the double-tracer technique (7) to examine the mechanism(s) via which M+S and each agent alone reduce the fasting and postmeal plasma glucose concentration in T2DM.     

Switching to Sulphonylureas in Children With iDEND Syndrome Caused by KCNJ11 Mutations Results in Improved Cerebellar Perfusion

OBJECTIVE

Activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the K_ATP channel, result in permanent neonatal diabetes mellitus. They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). Sulphonylurea (SU) treatment is reported to alleviate both the neurologic symptoms and diabetes in such cases. The study aimed to establish the magnitude and functional basis of the effect of SUs on the neurologic phenotype in children with iDEND using neuroimaging before and after insulin replacement with glibenclamide.

RESEARCH DESIGN AND METHODS

To localize and quantify the effect of glibenclamide administration, we performed single-photon emission computed tomography in seven patients with different mutations in KCNJ11. In five patients, measurements before and after initiation of SU treatment were performed.

RESULTS

Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region. Cerebellar perfusion improved for both left (P = 0.006) and right (P = 0.01) hemispheres, with the mean improvement being 26.7 ± 7.1% (n = 5). No patients showed deterioration of cerebellar perfusion on SU therapy. Electrophysiological studies revealed a good correlation between the magnitude of K_ATP channel dysfunction and the clinical phenotype; mutant channels with the greatest reduction in adenosine 5′-triphosphate inhibition were associated with the most severe neurologic symptoms.

CONCLUSIONS

We conclude it is likely that at least some of the beneficial effects of SU treatment on neurodevelopment in iDEND patients result from improved cerebellar perfusion.Approximately 50% of cases of permanent neonatal diabetes mellitus are caused by mutations in the genes encoding either the pore-forming (Kir6.2, KCNJ11) or regulatory (SUR1, ABCC8) subunits of the ATP-sensitive K⁺ (K_ATP) channel (1). In some patients with these mutations, neurologic symptoms such as mental retardation, impaired motor development, and hypotonia coexist with neonatal diabetes (iDEND syndrome); if epilepsy is also present, then the condition is called DEND syndrome (2). Previous studies have shown that it is possible to alleviate diabetes and some of the neurologic symptoms by substituting insulin therapy with orally ingested sulphonylurea (SU) drugs (3). In one patient, the improvement in neurologic function was associated with enhanced perfusion of the brain, particularly of the cerebellum, as measured by single-photon emission computed tomography (SPECT). To determine if this effect is common to patients treated with SU, we performed SPECT in patients with different mutations in KCNJ11 and varying clinical phenotypes.     

Auditory processing in children with normal and disordered speech

Phonological speech disorders are characterized by abnormal development towards the adult target pattern; its etiology is unknown. It is thought the this condition results from auditory processing disorders involving the abilities required for human beings to understand what is heard.AimTo investigate the relationship between auditory processing and the acquisition of disordered or normal speech, drawing comparisons between these profiles.Material and MethodA prospective, contemporary, cross-sectional study comprising a sample of 44 subjects aged 5 to 7 years; two groups were formed: a study group (SG) comprising children with disordered speech acquisition, and a control group (CG) consisting of children with normal speech acquisition. A simplified evaluation of auditory processing was undertaken: the PSI test in Portuguese; the speech-in-noise test; the binaural fusion test; the dichotic digit test; and the staggered spondaic word test (SSW).ResultsThere was a statistically significant difference between the two groups; the SG scored worse than the CG in all the tests. The PSI test only - with a 100% success rate - scored equally in both groups.ConclusionAuditory processing may affect speech development.     

A randomized,double‐blind,placebo‐controlled exploratory study to evaluate the potential of pycnogenol® for improving allergic rhinitis symptoms

The potential of Pycnogenol® for relieving allergic rhinitis (birch pollen) symptoms was explored in a double‐blind, placebo‐controlled trial. In 2008 19 subjects started treatment 3 weeks prior to the onset of birch pollen season in Ontario, Canada. While there was an improvement of eye and nasal symptoms with Pycnogenol, there was no significance versus placebo. It was postulated that Pycnogenol may require a lag‐time between the start of therapy and the onset of action. Therefore 39 subjects were treated 5–8 weeks prior to the 2009 birch allergy season. The evaluation of subjects in 2009 showed much lower scores for eye (?35%) and nasal (?20.5%) symptoms with Pycnogenol compared with placebo. In succession of the allergy season birch specific IgE increased by 31.9% in the placebo group compared with only 19.4% in the Pycnogenol group. Detailed analysis suggested that symptom‐relief was better the longer subjects were on Pycnogenol prior to the allergen exposure. The best results were found with subjects who took Pycnogenol 7–8 weeks ahead of the allergy season. With the limited number of 39 patients statistical predications were unattainable. In conclusion, Pycnogenol improved allergic rhinitis symptoms when supplementation was started at least 5 weeks before the onset of the allergy season. Copyright © 2010 John Wiley & Sons, Ltd.