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Presents a study on the effect of troglitazone on body fat distribution in type 2 diabetic patients. Research design and methods; Results; Conclusions.

Objective: We investigated the relationship between enhanced efficacy of incretin-related drugs with add-on SGLT2 inhibitor therapy in type 2 diabetic patients and their background characteristics. Patients and Methods: 1) Add-on SGLT2i therapy was given to a total of 15 type 2 diabetic patients with insufficient glycemic control despite conventional therapy including DPP-4i for 2 months in an outpatient setting. 2) Likewise, add-on SGLT2i therapy was given to a total of 17 type 2 diabetic patients with insufficient glycemic control despite conventional therapy including GLP-1RA for 3 months in an outpatient setting. In both groups, the glycemic variability (GV) was compared before and after add-on SGLT2i therapy by using CGM. GV indices evaluated included the difference before and after SGLT2i therapy in SD of 24-hour glucose values (ΔSD), the 24-hour total GV area (ΔSQ), and MAGE (ΔMAGE). Both groups were further divided according to the GV results by over 50th %tile and under 50th %tile into high-responders (n = 8 and 9) and low-responders (n = 7 and 8). Results: 1) Effect of add-on SGLT2i therapy on reductions in GV in those receiving DPP-4i: High-responders were shown to be associated with significantly higher mean glucose values, SD, SQ and MAGE than low-responders at baseline (P < 0.05). 2) Effect of add-on SGLT2i therapy on reductions in GV in those receiving GLP-1RA: high-responders were shown to be associated with significantly lower BMI, as well as significantly higher SD and SQ than low-responders at baseline (P < 0.05). Conclusions: With 2-month SGLT2i therapy as add-on to DPP-4i, reductions were seen in GV among patients with higher mean glucose and greater GV at baseline, suggesting a role for add-on SGLT2i therapy particularly in those with poor glycemic control. In contrast, with 3-month SGLT2i therapy as add-on to GLP-1RA, reductions were seen in GV among those with less severe obesity and greater GV at baseline. Disclosure: T. Onishi: None. Y. Shioda: None. Y. Mori: None. [ABSTRACT FROM AUTHOR]

Objective: We investigated the relationship between insulin withdrawal (IW), endogenous insulin recovery, and concurrent SGLT2 inhibitor (SGLT2i) therapy. Patients and Methods: Of the 78 type 2 diabetic patients admitted for glycemic control and subjected to meal tolerance tests (MTT) on the next day after admission and immediately before discharge using the same diabetes diet while off treatment, 39 patients who had received intensive insulin therapy after admission were subjected to retrospective analysis. Of these, 26 patients in whom insulin withdrawal had been achieved during admission were divided into those who had received concurrent SGLT2i therapy (n=19) and those who had not (n=7). Insulin secretion in terms of ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2 h during the MTT was compared at admission and discharge. Results: 1) While there was no significant difference between those with IW and those without IW in their age, BMI, HbA1c, C-peptide index and urinary CPR excretion at admission, significantly more patients with IW had received SGLT2i than those without IW (P < 0.001). Again, ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2 h were significantly (p<0.001) increased in those with IW but not in those without IW. 2) In those with IW, while ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2 h were significantly (p<0.05) increased in both of those with SGLT2i and those without, the time to IW was shown to be significantly shorter (p<0.01), the maximum daily insulin dose lower, and the duration of hospital stay shorter, in those with SGLT2i therapy than in those without. Conclusions: Study results confirmed that endogenous insulin secretion was significantly restored in those with IW and that the time to IW was significantly shorter in those with concurrent SGLT2i therapy than in those without, suggesting a role for SGLT2i in achieving IW. Disclosure: M. Matsui: None. H. Takahashi: None. S. Sawano: None. Y. Mori: None. K. Utsunomiya: None. [ABSTRACT FROM AUTHOR]

Objective: We investigated the acute effect of miglitol (M) on postprandial metabolic disorders as well as its chronic effect on insulin secretion using the spontaneously type 2 diabetic rat model. Methods: 1) Acute effect of single-dose M: After overnight fasting, 18-week-old OLETF rats were subjected to 2.5 g/kg sucrose loading and 2.0 g/kg fat loading. M 10 mg/kg was orally given to these animals shortly before sucrose and fat loading, with each group (group M) compared to the control rats (group C) orally given methylcellulose. 2) Chronic effect of M: M 50 mg/kg was mixed with chow and given to 10-week-old OLETF rats for 8 weeks. Results: 1) Acute effect of single-dose M: Post-sucrose challenge glucose and insulin levels were significantly lower in group M compared to those in group C. 'Post-fat challenge triglyceride values were also significantly lower in group M compared to those in group C. Of the lipoprotein fractious evaluated, chylomicron-TG values were shown to be significantly lower compared to those in group C. 2) Chronic effect of M: In 2g/kg OGTT at the end of study, post-glucose challenge glucose levels were significantly lower in group M compared to those in group C. While early insulin response to glucose challenge was not observed in group C, pre-glucose challenge insulin levels were significantly lower, and the 30-minute Δglucose/Δinsulin ratio significantly higher, in group M, compared to those in group C. TG and VLDL-TG levels were also significantly lower in group M compared to those in group C. While pancreatic islet hypertrophy, pancreatic islet cleavage by fibrotic tissue, and decreased β cells were observed in group C, no such change was observed in rats chronically given M. Conclusions: Single-dose M not only reduced post-sucrose challenge increases in glucose and insulin levels, but also suppressed post-fat-challenge increases in triglyceride levels in OLETF rats. Chronic M administration from pre-diabetic states onwards appeared to improve insulin resistance, preserve early insulin response, and protect against further impairment of glucose tolerance. [ABSTRACT FROM AUTHOR]

Objective: Postprandial hyperglycemia is often inadequately assessed in diabetes management. 1,5-anhydroglucitol (1,5-AG) as an index for urinary glucose is known to sensitively reflect glycemic excursions, as it varies even in relatively good glycemic states, and is thus thought to represent an appropriate index for evaluation of postprandial hyperglycemia. In this study, we investigated the relationship between postprandial hyperglycemia as assessed by self-monitoring of blood glucose and 1,5-AG in patients with moderately controlled diabetes. Methods: A total of 36 patients with type 2 diabetes aged 41 to 75 years of age with stable glycemic control whose HbA1c ranged between 5.5% and 8% were enrolled in the study. During the 1 month before their outpatient visits, glucose levels were measured in the subjects using a blood glucose meter before and after meals for a total of 6 times on 4 days within 1 week of each other. Based on these measurements, mean glucose, mean postprandial maximum glucose (MPMG), σ for postprandial glucose, σ for postprandial glucose above 180 mg/dL were analyzed to compare 1,5-AG, glycated albumin (GA), and HbA1c among the patients. Results: 1,5-AG varied considerably between the patients (10.9 ± 5.9µg/ml [mean ± SD]) despite similar HbA1c (6.5 ± 0.7%). 1,5-AG correlated more robustly with Z for postprandial glucose above 180 mg/dL than with HbA1c or GA. MPMG correlated more strongly with 1,5-AG than with HbA1c or GA. When divided into the upper (n = 18) and lower (n = 18) 50th percentile in terms of ∑ for postprandial glucose above 180 mg/dL, patients in the upper 50th percentile had significantly lower 1,5-AG values, and significantly higher MPMG values, compared to those in the lower 50th percentile, while there were no significant differences noted between the two groups in HbA1c and GA. Conclusions: 1,5-AG has been shown to reflect glycemic excursions, often in the postprandial state, more robustly than HbA1c or GA. 1,5-AG may prove useful as an adjunct marker to HbA1c in the assessment of glycemic control in patients with moderately controlled diabetes. [ABSTRACT FROM AUTHOR]

The angiotensin receptor blockers (ARBs) are reported to be insulin-sensitizers, and telmisartan is also reported in in vitro or animal studies as well as in clinical studies to have PPAR-γ-mediated insulin-sensitizing properties, unlike the other ARBs. In this study, telmisartan was examined for its effects on post-glucose challenge insulin response in hypertensive patients with obesity when they were switched from the other ARBs. Of the 22 hypertensive patients with BMI ≥ 25 being treated with ARBs other than telmisartan at our outpatient clinic, 14 patients who agreed to switch to telmiartan (TS group) were compared to 8 patients who stayed on the other ARBs (non-TS group). Patients were excluded if they were receiving oral hypoglycemic agents or insulin for diabetes mellitus (DM); if they had their blood pressure poorly controlled during the observation period; or if they switched their drug therapies. At baseline, 1 patient each was found to have NGT and IFG and 3 patients each were to have IGT and DM in the non-TS group, while 3, 1, 6 and 4 patients were found to have NGT, IFG, IGT and DM, respectively, in the TS group. BMI values in the TS and non-TS groups were 28.3 ± 3.4 and 26.3 ± 1.6, respectively. HbA1c values in the TS and non-TS groups were 5.6 ± 0.6 and 5.8 ± 0.5, respectively. There were no significant differences in all variables evaluated in the non-TS group at the end of the study compared to baseline. In contrast, TG values were found to be significantly lower, and HDL-C values significantly higher, in the TS group compared to baseline, while there were no significant differences noted in BMI, HbA1c and TC values. Furthermore, the 120-minute post-75 g OGTT glucose level and the area under the glucose curve 6 months after the start of treatment were significantly lower in the TS group compared to baseline, with the 60-, 90- and 180-minute post-challenge insulin levels and area under the insulin curve also significantly lower compared to baseline. It was suggested that telmisartan has a more favorable impact on insulin sensitization in hypertensive patients with obesity than the other ARBs. [ABSTRACT FROM AUTHOR]

The long-term effect of nateglinide administration on hepatic lipid accumulation and on insulin secretion was examined using the spontaneously diabetic rat model complicated by obesity. 10-week-old Otsuka Long Evans Tokushima Fatty (OLETF) rats were orally given nateglinide 50 mg/kg (NAT; n = 16), glibenclamide 2 mg/kg (GB; n = 16) or methylcellulose (MC-OLETF; n = 8) or subcutaneously injected insulin 2 U/kg (INS; n = 8), and normal control LETO rats orally given methylcellulose (MC-LETO; n = 8), twice daily immediately before feeding, under 1-hour restricted feeding, until they were 18-week-old. At the end of the study, 1 g/kg OGTT was performed in these rats. The triglyceride (TG) content was measured, and the expression of the hepatic lipid metabolism-related genes, SREBP1c, PPAR1α, SCD1, ACC, and the insulin secretion-related genes, insulin, SNAP25, Syntaxin 1A were evaluated by using the quantitative PCR method. 2-hour postprandial ,TG levels were significantly lower in the NAT and INS groups than in the MC-OLETF and GB groups after 1-hour feeding. While the TG content and the expression of the SCD1 gene were found to be significantly higher in all OLETF groups than in the MC-LETO group, these values were found to be significantly lower in the NAT group compared to the MC-OLETF group. There was no significant difference noted among all groups with regard to post-OGTT glucose levels. Pre-challenge and 15-minute post-challenge insulin levels were found to be significantly higher in the MC-OLETF and INS groups than in the MC-LETO group. However, no such excess insulin secretion was found in the NAT group which exhibited the insulin-secretory dynamics comparable to that seen in the MC-LETO group. The expression of the gene Syntaxin 1A was found to be significantly lower in the GB group than in the MC-OLETF group, no such down-regulation was noted in the NAT group. Study results suggest that long-term nateglinide administration not only inhibits the accumulation of TG in the liver but also works to preserve β-cell function from excess insulin secretion. [ABSTRACT FROM AUTHOR]

We previously reported that nateglinide suppresses increases in triglyceride (TG) after fat loading through suppression of not only exogenous but endogenous TG production. It is assumed that hepatic lipid metabolic disorders are implicated in increased endogenous TG, possibly leading in the long term to the development of fatty liver disease or nonalcoholic steatohepatitis (NASH). In this study, we investigated changes in hepatic fat content by using computed tomography (CT) in type 2 diabetic patients given nateglinide to evaluate the long-term effect of nateglinide on hepatic fat accumulation in these patients. Nateglinide (270 rag/day; t.i.d, before meals) was given to 18 drug-naïve patients with type 2 diabetes who were being treated on an outpatient basis (6 men, 12 women; age, 56 ± 7 years; BMI, 27.7 ± 4.4). Abdominal CT examinations were performed to evaluate liver/spleen (L/S) CT ratio, and visceral fat area (VFA) and subcutaneous fat area (SFA) at the umbilical level as assessed by slice-by-slice CT scanning, before and 6 months (M) after nateglinide administration in these patients. No significant changes were observed in BMI, VFA and SFA in the subjects. However, HbA1c values were significantly lower 3 and 6 months after the start of treatment, with the fasting glucose levels also tending to be lower, in these patients. ALT and AST values were also significantly lower in the subjects, with the L/S CT ratio by abdominal CT shown to be significantly increased 6 months after treatment compared to baseline. Of note, in 9 patients whose baseline L/S CT ratio was less than 0.8, the increase in L/S CT ratio was more pronounced (baseline: 0.58 ± 0.20 vs 6M: 0.78 ± 0.24, p < 0.01). Furthermore, there was a significant negative correlation between baseline L/S CT ratio and nateglinide-induced increases in L/S CT ratio (r = -0.58, p < 0.05). Long-term nateglinide administration suppressed hepatic fat accumulation in type 2 diabetic patients as in experimental animals. While the exact mechanisms for this remain unclear, given that this effect is not associated with changes in visceral fat area, it appears likely that nateglinide affects the liver directly. [ABSTRACT FROM AUTHOR]