alogliptin and Body-Weight

Alogliptin is the newest dipeptidyl peptidase 4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes either alone or in combination with other antidiabetic agents. The purpose of this review is to highlight the clinical studies that led to Food and Drug Administration approval of alogliptin and to provide insight into the place in therapy for the management of type 2 diabetes mellitus.. As a DPP-4 inhibitor, alogliptin raises postprandial levels of glucagon-like peptide 1, leading to insulin secretion and glucose homeostasis. When given as monotherapy, alogliptin has the ability to reduce glycoslate hemoglobin A1c (HbA1c) by 0.4% to 1.0%. Combination therapy yielded similar reductions with some variability depending on the agent with which alogliptin was combined. The mean HbA1c reduction seen with alogliptin is relative to the degree of HbA1c elevation at baseline. Alogliptin appears to be weight neutral and is relatively well tolerated with few adverse effects. Furthermore, alogliptin has proven to result in comparable efficacy and tolerability in the elderly as in the younger population.. Alogliptin alone or in combination with other antidiabetic agents has shown a significant reduction in HbA1c while remaining safe and tolerable. The efficacy profile of alogliptin is comparable to other DPP-4 inhibitors. Additional long-term research is necessary with regard to long-standing efficacy and effects on beta-cell function.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Piperidines; Randomized Controlled Trials as Topic; Uracil

As type 2 diabetes mellitus (T2DM) progresses, most patients will require insulin replacement therapy. Whether oral antidiabetic drug (OAD) therapy should be retained when initiating insulin is still debated. While the rationale to keep metformin with insulin is strong (mostly as an insulin-sparing agent to limit weight gain), the evidence is less clear for other OADs. In particular, the question now comes up what the expected benefit could be of combining the newer agents, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors with insulin. Additionally, when metformin is no longer a treatment option, as in the case of patients with severe renal impairment, insulin is often used as monotherapy, with little evidence of benefit in maintaining other OADs. In this specific situation, it is also of interest to evaluate the potential benefit of combined treatment with a DPP-4 inhibitor and insulin. Among the classic limitations of insulin therapy in patients with T2DM, hypoglycemia remains a major barrier to glycemic control, along with weight gain exacerbation. The oral DPP-4 inhibitors improve glycemic control by increasing the sensitivity of the islet cells to glucose, and thus are not associated with an increased risk for hypoglycemia and are weight neutral. In addition to the expected benefits associated with limiting insulin dose and regimen complexity, the specific advantages the DPP-4 inhibitor drug class on hypoglycemia and weight gain could justify combining DPP-4 inhibitors with insulin; additionally, a DPP-4 inhibitor may be of special value to decrease glycemic excursions that are not properly addressed by basal insulin therapy and metformin use, even after optimizing titration of the basal insulin. However, given the common original perception that treatment with DPP-4 inhibitors may be less beneficial with increasing disease progression because of the loss of β-cell function, the potential relevance of these agents in the setting of advanced T2DM treated with insulin was not necessarily anticipated. Promising data from studies on the use of these new agents in insulin-treated patients with T2DM have started to emerge. Our article provides a comprehensive overview of the currently available evidence from controlled randomized clinical trials and we discuss the potential role of DPP-4 inhibitors in the this setting. Further clinical experience will allow to fully assess the positioning of these agents in insulin-treated T2DM populations.

Topics: Adamantane; Body Weight; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drug Therapy, Combination; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

To evaluate the efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin plus metformin (A + M) initial combination therapy versus either as monotherapy in drug-naïve T2DM patients.. This international, randomized, double-blind, placebo-controlled, 26-week study involved T2DM patients with hyperglycaemia (HbA1c 7.5-10.0%) following diet/exercise therapy. Patients (N = 784) received placebo, alogliptin (A, 12.5 mg BID or 25 mg QD), metformin (M, 500 or 1000 mg BID) or A + M (12.5/500 or 12.5/1000 mg BID); placebo, A25 for secondary analyses only.. week 26 changes from baseline in HbA1c (primary), fasting plasma glucose (FPG) and 2-h postprandial glucose (PPG); incidences of clinical response and hyperglycaemic rescue.. Week 26 mean HbA1c reductions from baseline (8.45%) were -1.22 and -1.55% with A + M 12.5/500 and 12.5/1000 versus -0.56, -0.65, and -1.11% with A12.5, M500 and M1000 (p<0.001, A + M vs. component monotherapies). FPG reductions were -1.76 and -2.55 mmol/L with 12.5/500 and 12.5/1000 versus -0.54, -0.64 and -1.78 mmol/L with A12.5, M500 and M1000 (p < 0.05, A + M vs. component monotherapies). Significantly more A + M-treated patients achieved HbA1c < 7% (47.1-59.5% vs. 20.2-34.3% with monotherapy), significantly fewer required hyperglycaemic rescue (2.6-12.3% vs. 10.8-22.9% with monotherapy). A + M caused only mild/moderate hypoglycaemia (1.9-5.3%) and weight loss (0.6-1.2 kg).. Alogliptin plus metformin initial combination therapy was well tolerated yet more efficacious in controlling glycaemia in drug-naïve T2DM patients than either as monotherapy.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Uracil

To compare the efficacy and safety of alogliptin and placebo as add-on therapy in Japanese patients with type 2 diabetes who experienced inadequate glycemic control on voglibose plus diet/exercise therapy.. During an 8 week screening phase, patients aged ≥ 20 years were stabilized on voglibose 0.2 mg three times daily plus diet/exercise therapy. Those with HbA1c between ≥ 6.9% and <10.4% were randomly assigned to 12 weeks' double-blind treatment with once daily alogliptin 12.5 or 25 mg, or placebo. The primary endpoint was the change in HbA1c at 12 weeks from baseline. Patients then entered an open-label, 40 week extension trial (patients in the placebo group were randomly allocated to alogliptin 12.5 or 25 mg).. www.clinicaltrials.gov ; pivotal trial NCT01263483; Long term trial NCT01263509.. Least square mean change in HbA1c after 12 weeks' therapy from baseline (primary endpoint) was significantly greater in the alogliptin 12.5 mg (-0.96%; P < 0.0001) and 25 mg (-0.93%; P < 0.0001) groups compared with placebo (+0.06%). This was associated with statistically significant improvements in other measures of glycemic control, in particular sustained reductions in fasting plasma glucose and postprandial plasma glucose. These benefits were maintained for the duration of the 1 year study and, importantly, they were achieved without detrimental effects on tolerability/safety. In particular, there was no increase in the rate of hypoglycemia and almost no changes in mean body weight.. Addition of once daily alogliptin to voglibose monotherapy in Japanese patients with uncontrolled type 2 diabetes produced clinically significant improvements in glycemic control, and was well tolerated.

Topics: Adult; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Male; Middle Aged; Piperidines; Time Factors; Uracil

To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy.. After a 2-week screening period, adult patients 18-80 years of age entered a 4-week run-in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run-in period, patients were randomly assigned to double-blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end-point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end-points included clinical response rates and changes in fasting plasma glucose, beta-cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C-peptide, and homeostasis model assessment beta-cell function), body weight, and safety end-points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings].. The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (-0.38%) and 25 mg (-0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25-mg group had HbA1c levels < or =7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction > or =0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of beta-cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, -0.20 kg; alogliptin 12.5 mg, +0.60 kg; alogliptin 25 mg, +0.68 kg). AEs were reported for 63-64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0-2.5% across groups), and serious AEs (2.0-5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively.. In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Sulfonylurea Compounds; Uracil; Young Adult

The aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure.. Plasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5-400 mg) were used for the PK model development. One- and two-compartment models were evaluated as base structural PK models. The impact of selected covariates was assessed using stepwise forward selection and backward elimination procedures. The predictability and robustness of the final model was evaluated using visual predictive check and bootstrap analyses. The final model was used to perform simulations and guide appropriate dose adjustments.. A two-compartment model with first-order absorption and elimination best described the alogliptin concentration vs. time profiles. Creatinine clearance and weight had a statistically significant effect on the oral clearance (CL/F) of alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. Effect of weight on CL/F was not considered clinically relevant. Simulations at different doses of alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively.. The PK of alogliptin was well characterized by the model. The analysis suggested an alogliptin dose adjustment for subjects with moderate-to-severe renal impairment and no dose adjustments based on weight.

Topics: Adolescent; Adult; Aged; Biological Availability; Body Weight; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Kidney; Kidney Function Tests; Male; Middle Aged; Models, Biological; Piperidines; Tissue Distribution; Uracil; Young Adult

Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients.

Topics: Alzheimer Disease; Animals; Blood Glucose; Body Weight; Brain; Cytokines; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Gene Expression Regulation; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Nerve Tissue Proteins; Nitric Oxide Synthase Type II; Oxidative Stress; Piperidines; Rats; Rats, Zucker; Signal Transduction; Transcriptome; Uracil

Peroxisome proliferator-activated receptor-γ (PPARγ) agonists like pioglitazone (PGZ) are effective antidiabetic drugs, but they induce fluid retention and body weight (BW) gain. Dipeptidyl peptidase IV (DPP IV) inhibitors are antidiabetic drugs that enhance renal Na(+) and fluid excretion. Therefore, we examined whether the DPP IV inhibitor alogliptin (ALG) ameliorates PGZ-induced BW gain. Male Sv129 mice were treated with vehicle (repelleted diet), PGZ (220 mg/kg diet), ALG (300 mg/kg diet), or a combination of PGZ and ALG (PGZ + ALG) for 14 days. PGZ + ALG prevented the increase in BW observed with PGZ but did not attenuate the increase in body fluid content determined by bioimpedance spectroscopy (BIS). BIS revealed that ALG alone had no effect on fat mass (FM) but enhanced the FM-lowering effect of PGZ; MRI analysis confirmed the latter and showed reductions in visceral and inguinal subcutaneous (sc) white adipose tissue (WAT). ALG but not PGZ decreased food intake and plasma free fatty acid concentrations. Conversely, PGZ but not ALG increased mRNA expression of thermogenesis mediator uncoupling protein 1 in epididymal WAT. Adding ALG to PGZ treatment increased the abundance of multilocular cell islets in sc WAT, and PGZ + ALG increased the expression of brown-fat-like "beige" cell marker TMEM26 in sc WAT and interscapular brown adipose tissue and increased rectal temperature vs. vehicle. In summary, DPP IV inhibition did not attenuate PPARγ agonist-induced fluid retention but prevented BW gain by reducing FM. This involved ALG inhibition of food intake and was associated with food intake-independent synergistic effects of PPARγ agonism and DPP-IV inhibition on beige/brown fat cells and thermogenesis.

Topics: Adipocytes, Brown; Adipose Tissue, Brown; Animals; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Eating; Male; Mice; Pioglitazone; Piperidines; PPAR gamma; Thiazolidinediones; Uracil; Water-Electrolyte Balance

There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Humans; Hypoglycemic Agents; Insulin; Male; Pioglitazone; Piperidines; Rats; Thiazolidinediones; Uracil

Progressive β-cell dysfunction and loss of β-cell mass are fundamental pathogenic features of type 2 diabetes. To examine if anti-diabetic reagents, such as insulin, pioglitazone (pio), and alogliptin (alo), have protective effects on β-cell mass and function in vivo, we treated obese diabetic db/db mice with these reagents.. Male db/db mice were treated with a chow including pio, alo, or both of them from 8 to 16 weeks of age. Insulin glargine (gla) was daily injected subcutaneously during the same period.. At 16 weeks of age, untreated db/db mice revealed marked increase of HbA1c level, whereas those treated with pio, pio+alo, or insulin revealed the almost same HbA1c levels as non-diabetic db/m mice. Islet mass evaluated by direct counting in the whole pancreas and insulin content in isolated islets were preserved in pio, pio+alo and gla groups compared with untreated or alo groups, and there was no difference among pio, pio+alo and gla groups. To precisely evaluate islet β-cell functions, islet perifusion analysis was performed. In pio, pio+alo and gla groups, biphasic insulin secretion was preserved compared with untreated or alo groups. In particular, pio+alo as well as gla therapy preserved almost normal insulin secretion, although pio therapy improved partially. To examine the mechanism how these reagents exerted beneficial effects on β-cells, we evaluated expression levels of various factors which are potentially important for β-cell functions by real-time RT-PCR and immunohistochemistry. The results showed that expression levels of MafA and GLP-1 receptor were markedly decreased in untreated and alo groups, but not in pio, pio+alo and gla groups.. Combination therapy with pio and alo almost completely normalized β-cell functions in vivo, which was comparable with gla treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Body Weight; Deoxyguanosine; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Insulin, Long-Acting; Maf Transcription Factors, Large; Mice; Mice, Inbred C57BL; Pioglitazone; Piperidines; Receptors, Glucagon; Thiazolidinediones; Triglycerides; Uracil

The combination of two agents with different but complementary mechanisms of action is a logical approach for treating patients with type 2 diabetes. Thus, we evaluated chronic combination therapy with alogliptin, a highly selective dipeptidyl peptidase-4 inhibitor that enhances the action of incretins, and pioglitazone, a thiazolidinedione that improves peripheral and hepatic insulin sensitivity. Studies were designed to investigate the chronic metabolic and pancreatic effects of alogliptin (0.03%) plus pioglitazone (0.003%) combination treatment in obese ob/ob mice. After 4-5 weeks of treatment, alogliptin significantly increased plasma active glucagon-like peptide-1 levels up to 4.1-fold and decreased plasma glucagon up to 25%, whereas pioglitazone significantly increased plasma adiponectin up to 1.3-fold. Combination treatment exhibited a complementary effect, increasing plasma insulin levels by 3.2-fold (alogliptin alone, 1.6-fold; pioglitazone alone, 1.5-fold) and decreasing glycosylated hemoglobin by 2.3% (alogliptin alone, 1.0%; pioglitazone alone, 1.5%), and non-fasting and fasting plasma glucose by 37% and 62% (alogliptin alone, 17% and 24%; pioglitazone alone, 30% and 45%), respectively. Combination treatment also decreased plasma triglycerides by 67% and non-esterified fatty acids by 25% (alogliptin alone, 24% and 11%; pioglitazone alone, 54% and 8%). Moreover, combination treatment increased pancreatic insulin content by 2.2-fold (alogliptin alone, 1.3-fold; pioglitazone alone, 1.6-fold), with no significant changes in body weight. These results indicate that combination treatment with alogliptin and pioglitazone improved glycemic control, lipid profiles and increased pancreatic insulin content in ob/ob mice by preventing incretin inactivation and improving insulin resistance. These results provide a strong argument for using alogliptin in combination with pioglitazone.

Topics: Animals; Blood Glucose; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Eating; Enzyme Inhibitors; Hormones; Hyperinsulinism; Insulin; Lipids; Male; Mice; Mice, Obese; Pancreas; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

Alogliptin, a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, enhances incretin action and pioglitazone enhances hepatic and peripheral insulin actions. Here, we have evaluated the effects of combining these agents in diabetic mice.. Effects of short-term treatment with alogliptin alone (0.01%-0.1% in diet), and chronic combination treatment with alogliptin (0.03% in diet) and pioglitazone (0.0075% in diet) were evaluated in db/db mice exhibiting early stages of diabetes.. Alogliptin inhibited plasma DPP-4 activity up to 84% and increased plasma active glucagon-like peptide-1 by 4.4- to 4.9-fold. Unexpectedly, alogliptin alone lacked clear efficacy for improving glucose levels. However, alogliptin in combination with pioglitazone clearly enhanced the effects of pioglitazone alone. After 3-4 weeks of treatment, combination treatment increased plasma insulin by 3.8-fold, decreased plasma glucagon by 41%, both of which were greater than each drug alone, and increased plasma adiponectin by 2.4-fold. In addition, combination treatment decreased glycosylated haemoglobin by 2.2%, plasma glucose by 52%, plasma triglycerides by 77% and non-esterified fatty acids by 48%, all of which were greater than each drug alone. Combination treatment also increased expression of insulin and pancreatic and duodenal homeobox 1 (PDX1), maintained normal beta-cell/alpha-cell distribution in islets and restored pancreatic insulin content to levels comparable to non-diabetic mice.. These results indicate that combination treatment with alogliptin and pioglitazone at an early stage of diabetes improved metabolic profiles and indices that measure beta-cell function, and maintained islet structure in db/db mice, compared with either alogliptin or pioglitazone monotherapy.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Cell Degranulation; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Eating; Glucagon; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Lipids; Male; Mice; Pioglitazone; Piperidines; Thiazolidinediones; Uracil