ObjectiveTo determine real-world trends in antidiabetic drug use, and persistence and adherence, in Japanese patients with type 2 diabetes mellitus (T2DM).DesignRetrospective evaluation of administrative claims data (2011–2015) using the Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases.SettingAnalysis of two administrative claims databases for Japanese patients with T2DM.ParticipantsAdults (aged ≥18 years) with an International Classification of Diseases, 10th Revision code of T2DM and at least one antidiabetic drug prescription.Main outcome measuresTreatment patterns in untreated (UT) or previously treated (PT) patients receiving antidiabetic therapy; persistence with treatment at 12 months; adherence to treatment at 12 months.Results40 908 and 90 421 patients were included from the JMDC and MDV databases, respectively. The most frequently prescribed therapy at the index (first prescription) date was dipeptidyl peptidase-4 inhibitor (DPP-4i) in UT patients (JMDC: 44.0%, MDV: 54.8%) and combination therapy in PT patients (74.6%, 81.1%). Most common combinations were DPP-4i plus: biguanide (BG; 11.4%, 10.9%), sulfonylurea (SU; 8.4%, 11.0%) or BG+SU (7.8%, 9.1%). In UT or PT patients from either database whose index prescription was for any antidiabetic drug class(es) other than DPP-4i, the most frequent add-on or switch was to DPP-4i. 12-month persistence with index monotherapy was highest with DPP-4i and BG. Adherence was high (≥80%) for all monotherapy schedules, except insulin and glucagon-like peptide-1 agonist, and for the five most frequent two-drug and three-drug combinations. Persistence was greater in elderly UT patients and in those receiving ≤5 medications, but comparatively worse in UT patients with ≥3 index antidiabetic drug classes.ConclusionsThe findings indicate that DPP-4i is the most commonly used antidiabetic drug class in Japanese patients with T2DM, and persistence and adherence to this antidiabetic drug class are high.

SummaryThe present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol. kg-1) or orally (5.0 mmolkg-1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol. kg -1) and oral administration of either delapril or enalapril (5.0 mmol.kg -1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-a-adamantaneacetyl-DArg-[Hyp3,ThiJ.8,D-Phe 7]-bradykinin) (0.5 nmol. kg-1. min -1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol. kg-1. min-1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol. kg-1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group. Bradykinin may also possibly be involved in the mechanism underlying the improvement in insulin sensitivity associated with ACE-inhibition. [Diabetologia (1994) 37: 300-307]

The present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol.kg-1) or orally (5.0 mmol.kg-1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol.kg-1) and oral administration of either delapril or enalapril (5.0 mmol.kg-1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-alpha-adamantane-acetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]-b bradykinin) (0.5 nmol.kg-1 x min-1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol.kg-1 x min-1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol.kg-1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group.(ABSTRACT TRUNCATED AT 250 WORDS)

SummaryIn pancreatic alpha cells, the existence and function of the insulin receptor has not yet been fully established. In this study, to confirm the expression of functional insulin receptors in pancreatic alpha cells, we performed: 1)insulin receptor binding assay, 2) Northern blot analysis and RT-PCR (reverse transcription-polymerase chain reaction) amplification of insulin receptor mRNA, 3) immunocytochemical staining, 4) biosynthetic labelling of insulin receptor protein using [35S]methionine, 5) analysis of insulinstimulated autophosphorylation of the insulin receptor in glucagon secreting cell lines, In-R1-G9 and c~TC clone 6 cells. Glucagon secretion decreased with the addition of insulin in both cells. The receptor binding studies using [12SI-Tyr-A14] insulin revealed that both cells possessed a significant number of insulin receptors (In-R1-G9: K 1 = 2.1 x 109 mol/1-1, K 2 = 6.2 x 107 mol/1-1, R 1 = 0.27 x 10 4, R 2 = 1.86 x 10 4 sites/cell; aTC clone 6: K s = 2.1 x 109 mol/1-1, K 2 = 7.3 x 107 mol/1-1, R 1 = 0.27 • 10 4, R2 = 1.95 x 10 4 sites/cell). Northern blot analysis as well as RT-PCR amplification showed the mRNA specific for insulin receptor in both cells. By immunocytochemical staining using anti-insulin receptor a-subunit antibody, positive immunostaining for insulin receptor was observed in both cells.[35S]Methionine labelling of both cells followed by immunoprecipitation using anti-insulin receptor antibody showed the correct size of the insulin receptor protein. The insulin receptor expressed in these cells underwent autophosphorylation by insulin stimulation. It is concluded that functional insulin receptors are properly expressed in In-R1-G9 and aTC clone 6 cells.Key words Pancreatic alpha cell, In-R1-G9, aTC clone 6, insulin receptor, glucagon secretion [Diabetologia (1995) 38: 422-429] It is well-known that optimal administration of insulin normalizes a paradoxical rise, after an oral glucose load and an exaggerated rise during intravenous arginine infusion, in plasma glucagon secretion in either hypoinsulinaemic or hyperinsulinaemic diabetic pa-

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