Effective long-term treatment of Type 2 Diabetes Mellitus (T2DM) implies modification of the disease processes that cause this progressive disorder. This paper proposes a mechanism-based approach to disease progression modeling of T2DM that aims to provide the ability to describe and quantify the effects of treatment on the time-course of the progressive loss of beta-cell function and insulin-sensitivity underlying T2DM. It develops a population pharmacodynamic model that incorporates mechanism-based representations of the homeostatic feedback relationships between fasting levels of plasma glucose (FPG) and fasting serum insulin (FSI), and the physiological feed-forward relationship between FPG and glycosylated hemoglobin A1c (HbA1c). This model was developed on data from two parallel one-year studies comparing the effects of pioglitazone relative to metformin or sulfonylurea treatment in 2,408 treatment-naïve T2DM patients. It was found that the model provided accurate descriptions of the time-courses of FPG and HbA1c for different treatment arms. It allowed the identification of the long-term effects of different treatments on loss of beta-cell function and insulin-sensitivity, independently from their immediate anti-hyperglycemic effects modeled at their specific sites of action. Hence it avoided the confounding of these effects that is inherent in point estimates of beta-cell function and insulin-sensitivity such as the widely used HOMA-%B and HOMA-%S. It was also found that metformin therapy did not result in a reduction in FSI levels in conjunction with reduced FPG levels, as expected for an insulin-sensitizer, whereas pioglitazone therapy did. It is concluded that, although its current implementation leaves room for further improvement, the mechanism-based approach presented here constitutes a promising conceptual advance in the study of T2DM disease progression and disease modification.

Aims/hypothesis: The aim of this analysis was to examine the long-term effects of pioglitazone or gliclazide addition to failing metformin monotherapy and pioglitazone or metformin addition to failing sulphonylurea monotherapy in patients with type 2 diabetes. Methods: Two 2-year, randomised, multicentre trials were performed in patients with inadequately controlled type 2 diabetes (HbA 1 c 7.5-11% inclusive), who were receiving either metformin or a sulphonylurea at ≥50% of the maximum recommended dose or at the maximum tolerated dose. In the first study, patients on metformin received add-on therapy with pioglitazone (15-45 mg/day, n=317) or gliclazide (80-320 mg/ day, n=313). In the second study, patients on sulphonylurea therapy were randomised to receive add-on therapy with either pioglitazone (15-45 mg/day, n=319) or metformin (850-2,550 mg/day, n=320). HbA 1 c, fasting plasma glucose, insulin and lipids were investigated. Results: At week 104, the mean reduction from baseline in HbA 1 c was 0.89% for pioglitazone and 0.77% for gliclazide addition to metformin (p=0.200). There was a statistically significant between-group difference for the change in mean fasting plasma glucose at week 104 (−1.8 mmol/l for pioglitazone vs −1.1 mmol/l for gliclazide, p<0.001). There were no significant differences in changes from baseline in glycaemic parameters for pioglitazone compared with metformin addition to sulphonylurea therapy. Whether added to metformin or sulphonylurea, pioglitazone caused significantly greater decreases in triglycerides and significantly greater increases in HDL cholesterol than the comparator regimens (p≤0.001). There were decreases in LDL cholesterol in the comparator groups and these were significantly different from the small changes observed with pioglitazone (p<0.001). All treatment regimens were well tolerated. There were weight increases of 2.5 kg and 3.7 kg in the pioglitazone and 1.2 kg in the gliclazide add-on groups, and there was a mean decrease of 1.7 kg in the metformin add-on group. Conclusions/interpretation: As add-on therapy to existing sulphonylurea or metformin therapy, pioglitazone improved glycaemic control and this improvement was sustained over 2 years. Furthermore, there were potential benefits in terms of improvements in specific lipid abnormalities. This could offer an advantage over the addition of other oral agents in the long-term treatment of diabetes.

MicroRNAs (miRNAs) are short non-coding RNA species which are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of diabetic nephropathy. miRNAs are present in urine in a remarkably stable form packaged in extracellular vesicles, predominantly exosomes. In the present study, urinary exosomal miRNA profiling was conducted in urinary exosomes obtained from 8 healthy controls (C), 8 patients with type II diabetes (T2D) and 8 patients with type II diabetic nephropathy (DN) using Agilent´s miRNA microarrays. In total, the expression of 16 miRNA species was deregulated (>2-fold) in DN patients compared to healthy donors and T2D patients: the expression of 14 miRNAs (miR-320c, miR-6068, miR-1234-5p, miR-6133, miR-4270, miR-4739, miR-371b-5p, miR-638, miR-572, miR-1227-5p, miR-6126, miR-1915-5p, miR-4778-5p and miR-2861) was up-regulated whereas the expression of 2 miRNAs (miR-30d-5p and miR-30e-5p) was down-regulated. Most of the deregulated miRNAs are involved in progression of renal diseases. Deregulation of urinary exosomal miRNAs occurred in micro-albuminuric DN patients but not in normo-albuminuric DN patients. We used qRT-PCR based analysis of the most strongly up-regulated miRNAs in urinary exosomes from DN patients, miRNAs miR-320c and miR-6068. The correlation of miRNA expression and micro-albuminuria levels could be replicated in a confirmation cohort. In conclusion, urinary exosomal miRNA content is altered in type II diabetic patients with DN. Deregulated miR-320c, which might have an impact on the TGF-β-signaling pathway via targeting thrombospondin 1 (TSP-1) shows promise as a novel candidate marker for disease progression in type II DN that should be evaluated in future studies.

FOR THE GLAL STUDY GROUPOBJECTIVE -The hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control for up to 2 years in patients with type 2 diabetes was tested.RESEARCH DESIGN AND METHODS -This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study. Approximately 600 patients from 98 centers participated. Eligible patients had completed a previous 12-month study and consented to continue treatment for a further year. To avoid selection bias, all patients from all centers were included in the primary analysis (a comparison of the time-to-failure distributions of the two groups by using a log-rank test) regardless of whether they continued treatment for a 2nd year. By using repeated-measures ANOVA, time course of least square means of HbA 1c and homeostasis model of assessment (HOMA) indexes (HOMA-%S and HOMA-%B) were analyzed.RESULTS -A greater proportion of patients treated with pioglitazone maintained HbA 1c Ͻ8% over the 2-year period than those treated with gliclazide. A difference between the KaplanMeier curves was apparent as early as week 32 and widened at each time point thereafter, becoming statistically significant from week 52 onward. At week 104, 129 (47.8%) of 270 pioglitazone-treated patients and 110 (37.0%) of 297 gliclazide-treated patients maintained HbA 1c Ͻ8%. Compared with gliclazide treatment, pioglitazone treatment produced a larger decrease in HbA 1c , a larger increase in HOMA-%S, and a smaller increase in HOMA-%B during the 2nd year of treatment.CONCLUSIONS -Pioglitazone is superior to gliclazide in sustaining glycemic control in patients with type 2 diabetes during the 2nd year of treatment. Diabetes Care 28:544 -550, 2005T ype 2 diabetes, with its core defects of insulin resistance and relative insulin deficiency, is a progressive disease. Insulin resistance remains generally stable throughout the natural history of the disease, but there is a progressive loss of glycemic control due to the continuing loss of ␤-cell function. The U.K. Prospective Diabetes Study (1) showed that at diagnosis, patients have already lost ϳ50% of their ␤-cell function, which was further reduced to ϳ30% at 5 years.The standard approach at initial diagnosis for many patients with type 2 diabetes is a prescription of diet and physical activity to correct their hyperglycemia. When glycemic targets cannot be attained or maintained with this approach, an oral antihyperglycemic medication (OAM) is added to the lifestyle regimen. When monotherapy fails, treatment is changed to combination OAM therapy, OAMs plus insulin, or insulin therapy (2). Most patients initially respond to OAM monotherapy when they use it. However, with continued therapy, some patients can no longer achieve their glycemic target. The inability to maintain the glycemic target may indicate progression of disease rather than lack of response to a drug (3,4).Sulfonylureas, first introduced in the mid-1950s, are commonly used as monotherapy in patients with type 2 diabete...

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