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2.
Endocrine ; 56(1): 212-216, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28303514

ABSTRACT

Diabetic ketoacidosis is an infrequent but life-threatening acute complication of diabetes, affecting predominantly patients with type 1 diabetes, children, and pregnant women, where ketosis is usually associated with marked hyperglycemia. Recently, an increasing number of cases have been reported of euglycemic diabetic ketoacidosis in patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitor treatment in routine practice. There is a minor, but not negligible diabetic ketoacidosis risk associated with this drug class, which was not seen in randomized clinical trials. However, sodium-glucose cotransporter2 inhibitors increase the risk of ketosis by increasing glucagon secretion in the pancreas and decreasing the renal excretion of 3-hydroxybutyrate and acetoacetate. When used in addition to insulin, any insulin dose reduction required to avoid hypoglycemia may lead to insufficient suppression of lipolysis and ketogenesis. sodium-glucose cotransporter2 inhibitor-induced loss of urinary glucose encourages euglycemia. Normo-glycemic or near-normoglycemic diabetic ketoacidosis represents a major threat to the health and well-being of a patient, because it may occur undetected and without any indicative hyperglycemia. In consequence, patients on sodium-glucose cotransporter2 inhibitors are recommended to perform regular blood ketone tests since they are not alerted to incipient diabetic ketoacidosis by glucose testing alone. This option is offered by several blood glucose meters that can also measure ketones with a separate ketone strip or in one case by an automatic parallel ketone assessment from the same strip. The need for extra testing and the associated costs may be a barrier to patient acceptance of this risk mitigation procedure. However, patients who are at risk for euglycemic diabetic ketoacidosis when being treated with sodium-glucose cotransporter2 inhibitors should be specially advised to monitor blood ketone levels on a regular basis.


Subject(s)
Benzhydryl Compounds/adverse effects , Canagliflozin/adverse effects , Diabetes Mellitus, Type 2/drug therapy , Diabetic Ketoacidosis/etiology , Glucosides/adverse effects , Hypoglycemic Agents/adverse effects , Sodium-Glucose Transport Proteins/antagonists & inhibitors , Benzhydryl Compounds/therapeutic use , Canagliflozin/therapeutic use , Glucosides/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use
3.
Theriogenology ; 86(3): 862-7, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27084555

ABSTRACT

Various attempts were made to improve the diagnosis of the periparturient hypogalactia syndrome in sows. A new approach was the detection of elevated concentrations of acute phase proteins. The objective of our study was to investigate the serum concentrations of haptoglobin (Hp) and C-reactive protein (CRP) in sows on Day 7 postpartum and relationship to body temperature. From Day 1 to Day 6 postpartum, 199 sows were clinically examined and a blood sample was taken for measuring Hp and CRP at Day 7. The median of Hp and CRP were 1.83 mg/mL (interquartile range: 1.42-2.13 mg/mL) and 60.0 µg/mL (interquartile range: 15.2-216.5 µg/mL). We did not find a correlation between Hp and CRP (ρ = 0.11, P = 0.12) nor a difference between sows categorized as ill and healthy sows in Hp concentration (P = 0.1) and CRP (P = 0.34). Sows with Hp > 2.13 mg/mL had a higher rectal temperature than sows with Hp ≤ 2.13 mg/mL (P = 0.037), but there was no difference in vaginal temperature (P = 0.24). Regarding CRP, sows with CRP greater than 216.5 µg/mL had higher rectal temperature (P = 0.017) and vaginal temperature (P = 0.02) than sows with CRP ≤ 216.5 µg/mL. As demonstrated in this study, Hp and CRP do not support the detection of early postpartum disorders in sows.


Subject(s)
Body Temperature/physiology , C-Reactive Protein/metabolism , Haptoglobins/metabolism , Postpartum Period/blood , Swine/blood , Animals , Female , Postpartum Period/physiology , Rectum , Swine/physiology , Vagina
4.
Curr Med Res Opin ; 30(10): 2001-8, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24940825

ABSTRACT

OBJECTIVES: Use of an injection site modulation device (InsuPad) in intensive insulin treatment reduces frequency of hypoglycemia and prandial insulin requirements by enhancing subcutaneous microcirculation. This meal tolerance test (MTT) investigation was performed as a sub-study during the real-world BARMER study to demonstrate non-inferiority of the reduced insulin doses observed in this study with respect to metabolic control. METHODS: The MTT was performed at baseline and after 3 months in insulin treated diabetes patients using the modulation device vs. a control group without device. The dose used for the MTT was individually calculated based on the prandial insulin records from the patient diaries before the test. Blood was drawn for determination of glucose, insulin, C-peptide, proinsulin, triglycerides, free fatty acids, nitrotyrosine, and asymmetric dimethyl-arginine (ADMA) at multiple time-points from 0 to 300 min. A total of 32 patients from one site were included into this MTT study (8 female, 7 type 1 diabetes, age: 49.9 ± 12.5 yrs, HbA1c: 7.2 ± 0.5%). RESULTS: During the BARMER study, mean HbA1c was treated to target (<6.5%) in both groups. The prandial insulin dose decreased in the MTT modulation device group by -17.1%, but remained unchanged in the control group (-0.1%, p < 0.001). No change was seen for the basal insulin dose in both treatment arms. There were no differences between the groups with respect to the postprandial curves for glucose, C-peptide, intact proinsulin, free fatty acids, and triglycerides. Insulin absorption was faster with the modulation device (Tmax: 60 ± 28 min vs. 99 ± 46 min, p < 0.05). Key limitations are the small patient sample size and impossibility to determine the short-term effects of device use. CONCLUSIONS: The results of this meal tolerance sub-study confirm that the observed prandial insulin dose reduction when using the injection site modulation device has no negative impact on postprandial metabolism.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Drug Delivery Systems/methods , Injections, Subcutaneous/methods , Insulin , Adult , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 2/blood , Dose-Response Relationship, Drug , Drug Monitoring , Female , Glycated Hemoglobin/analysis , Humans , Hypoglycemia/chemically induced , Hypoglycemia/prevention & control , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/adverse effects , Insulin/administration & dosage , Insulin/adverse effects , Male , Middle Aged , Treatment Outcome
5.
Curr Med Res Opin ; 30(5): 753-60, 2014 May.
Article in English | MEDLINE | ID: mdl-24392996

ABSTRACT

BACKGROUND: The primary objective of this prospective controlled study was to investigate the impact of standardized injection-site warming on prandial rapid acting insulin dose and glycemic control when studied under real-world conditions. METHODS: All 145 participating patients (51 female, 94 male, 13 type 1 and 132 type 2 patients, age: 61.6 ± 8.4 yrs, HbA1c: 7.19 ± 0.50%) were treated with intensive insulin glargine and short-acting insulin analog therapy. After a 4 week treatment optimization run-in period, patients were randomized to continue therapy for three months without (control) or with a local injection-site warming device (InsuPad * ). Observation parameters included HbA1c, insulin dose, frequency of hypoglycemia, body weight and adverse events. RESULTS: HbA1c improved in both arms until study end (control group: 6.3 ± 0.5%; injection-site warming device: 6.3 ± 0.5%; both p < 0.001 vs. baseline). To achieve this good control, patients in the control group needed to increase the daily prandial insulin dose by 8.1% (from 66 ± 31 U to 71 ± 38 U, p < 0.05) with stable basal insulin requirements. Patients who used the injection-site warming device required less prandial insulin (70 ± 43 U to 55 ± 34 U; -19%, p < 0.001) and slightly more basal insulin (+3.9%). Total daily insulin dose increased in the control group (+3.7%) and decreased with warming device use (-8.6%, p < 0.001). The number of hypoglycemic events (<63 mg/dL) during the observation period was higher in the control group (6.2 ± 9.9/patient vs. injection-site warming device: 3.3 ± 4.8/patient, p < 0.05). Main study limitations can be seen in the open label design reliability of the collected dose information and the very obese patient cohort. CONCLUSION: When treating obese patients to target with insulin therapy, use of an injection-site warming device for 3 months resulted in a lower frequency of hypoglycemic events and a reduction in prandial insulin analog requirements. If these results are confirmed in other patient populations, an injection-site warming device may be useful in achieving treatment targets with a safer and more efficient basal bolus therapy in insulin-treated patients with type 1 and type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hyperthermia, Induced/methods , Hypoglycemia/prevention & control , Hypoglycemic Agents/administration & dosage , Insulin, Long-Acting/administration & dosage , Obesity/blood , Absorption , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Female , Humans , Hypoglycemia/blood , Hypoglycemic Agents/pharmacokinetics , Insulin Glargine , Insulin, Long-Acting/pharmacokinetics , Male , Middle Aged , Obesity/metabolism , Postprandial Period , Prospective Studies
6.
Curr Med Res Opin ; 30(2): 185-90, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24156775

ABSTRACT

Since 2003, blood glucose meters for patient self testing are approved in Europe based on the accuracy performance criteria as defined by the ISO15197 guideline. A new draft ISO guideline is currently under regulatory review, which suggests more strict accuracy acceptance criteria, and which may not be entirely fulfilled by currently commercialized blood glucose meter systems. In order to investigate the compliance of BG*Star and iBG*Star and several other blood glucose meters with the new draft ISO guideline, we performed a post-hoc analysis of data obtained from a recently performed ISO-conforming clinical accuracy performance study. This study was performed with 106 patients, clinically presenting with blood glucose levels distributed over the entire measurement range and in line with the glucose distribution requirements as demanded by the guideline. The YSI 2300 STAT Plus analyzer (glucose oxidase) served as reference method. While all tested meters had been in a high degree of compliance with the current ISO criteria, performance was lower when analyzed in accordance with the new acceptance criteria (95% of readings have to be within ±15 mg/dL for values <100 mg/dL, and within ±15% for values ≥100 mg/dL). The following meters met the new criteria: Accu-Chek Aviva (95.5%/98.6%), BG*Star (98.5%/97.3%), iBG*Star (98.5%/97.3%), FreeStyle Freedom Lite (95.5%/96.6%), and OneTouch Ultra2 (95.5%/96.5%). One meter failed with low blood glucose values (Contour: 90.9%/95.9%). In conclusion, BG*Star and iBG*Star and several other branded meters met the new draft ISO15197 acceptance criteria, when tested in accordance with the instructions for use and with the ISO accuracy testing protocol in a clinical setting.


Subject(s)
Blood Glucose Self-Monitoring/instrumentation , Blood Glucose/analysis , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 2/diagnosis , Guideline Adherence , Adolescent , Adult , Aged , Blood Glucose Self-Monitoring/standards , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 2/blood , Europe , Female , Humans , Male , Middle Aged , Young Adult
7.
Article in German | MEDLINE | ID: mdl-23959617

ABSTRACT

OBJECTIVE: Postpartum diseases of sows are economically important in the pig industry. They affect animal health and welfare of sows and piglets. Measuring rectal temperature in sows post partum is a commonly used diagnostic method to early detection of infectious diseases. The study consisted of five parts. The objective of the first four parts was to evaluate the influence of different factors on the measurements of rectal temperature (e.g. investigator, thermometer, penetration depth of the thermometer). The secondary objective of this study was to validate the application of a temperature logger to continuously measure vaginal temperature. MATERIAL AND METHODS: Thirty sows on the first day postpartum were used in the first four parts of the study. Rectal temperature was measured repeatedly by one investigator, by different investigators, with different thermometers and at different penetration depths. For the fifth part of the study 21 sows on the first day postpartum were used. A temperature logger was inserted in the vagina for a duration of 6 hours. Additionally, rectal temperature was measured. RESULTS: The data showed that rectal temperature can be measured repeatably (mean ± standard deviation = 38.7 ± 0.1 °C, coefficient of variation = 0.2%). Different investigators or thermometers resulted in low differences (0.0 °C and 0.1 °C). The penetration depth of the thermometer influenced the result (difference of 0.4 °C between 5 and 10 cm). Rectal and vaginal temperatures, measured in 21 sows, were highly correlated (r = 0.80, p < 0.01) with a mean difference of 0.3 °C. CONCLUSION AND CLINICAL RELEVANCE: Rectal temperature measurement can be regarded as a repeatable diagnostic method. The measurement should be standardized (type of thermometer, penetration depth). The measurement of vaginal temperature with a data logger in early puerperal sows is a possible means for a continuous and non-invasive monitoring of body temperature.


Subject(s)
Body Temperature/physiology , Postpartum Period/physiology , Swine Diseases/physiopathology , Thermometry/veterinary , Animals , Female , Physical Examination , Puerperal Disorders/diagnosis , Puerperal Disorders/physiopathology , Puerperal Disorders/veterinary , Rectum/physiology , Sus scrofa , Swine , Swine Diseases/diagnosis , Thermometry/methods , Thermometry/standards , Vagina/physiology
8.
Diabetes Obes Metab ; 15(6): 576-9, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23384119

ABSTRACT

This study compared the effect of Glimepiride versus Vildagliptin on ß-cell function and the release of intact proinsulin (PI) in patients with type 2 diabetes mellitus. Patients on metformin monotherapy were randomized to add on treatment with Vildagliptin or Glimepiride. A standardized test meal was given at baseline, after 12 and 24 weeks of treatment. Insulin, PI and blood glucose values were measured in the fasting state and postprandial for 300 min. Fasting PI levels significantly decreased in the Vildagliptin group. The area under the curve for the postprandial release of PI decreased during Vildagliptin and increased during Glimepiride treatment. The proinsulin to insulin ratio declined in the Vildagliptin group, whereas it did not change significantly in the Glimepiride group. Addition of Vildagliptin to ongoing Metformin treatment reconstitutes the disproportionality of the proinsulin to insulin secretion from the ß cell.


Subject(s)
Adamantane/analogs & derivatives , Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Hypoglycemic Agents/administration & dosage , Metformin/administration & dosage , Nitriles/administration & dosage , Proinsulin/drug effects , Pyrrolidines/administration & dosage , Sulfonylurea Compounds/administration & dosage , Adamantane/administration & dosage , Area Under Curve , Diabetes Mellitus, Type 2/blood , Drug Therapy, Combination , Female , Humans , Male , Postprandial Period , Proinsulin/metabolism , Treatment Outcome , Vildagliptin
9.
Diabetes Obes Metab ; 14(11): 1000-9, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22686944

ABSTRACT

AIMS: To evaluate the efficacy and safety of rivoglitazone, a peroxisome proliferator-activated receptor γ agonist in the thiazolidinedione class, in subjects with suboptimally controlled type 2 diabetes mellitus (T2DM). METHODS: Subjects aged ≥18 years with T2DM and haemoglobin A1c (HbA1c) >7.0% and ≤8.5%, who were treatment naïve or receiving a non-thiazolidinedione antidiabetes monotherapy, entered a 2-week washout and single-blind placebo run-in period and were then randomized 2 : 4 : 11 : 11 to double-blind treatment with placebo, rivoglitazone 1.0 mg/day, rivoglitazone 1.5 mg/day, or pioglitazone 45 mg/day, for 26 weeks. RESULTS: A total of 1912 subjects received placebo (n = 137), rivoglitazone 1.0 mg (n = 274), rivoglitazone 1.5 mg (n = 750) or pioglitazone (n = 751). Rivoglitazone 1.5 mg was statistically superior (p = 0.0339) and rivoglitazone 1.0 mg was non-inferior (p = 0.0339) to pioglitazone in reducing HbA1c from baseline (changes of -0.7%, -0.4% and -0.6%, respectively). Rivoglitazone also significantly reduced fasting plasma glucose from baseline (p < 0.0001). Rivoglitazone significantly improved estimates of insulin sensitivity, high-density lipoprotein cholesterol levels, and other metabolic and inflammatory biomarkers. Rivoglitazone was generally well tolerated at both doses, with treatment-emergent adverse event (TEAE) rates similar to pioglitazone. The most common drug-related TEAEs were peripheral oedema (active, 5.2-6.2%; placebo 0.7%), increased weight (active, 1.6-3.1%; placebo, 0%) and pitting oedema (active, 1.3-2.2%; placebo, 0%). CONCLUSIONS: In subjects with suboptimally controlled T2DM, rivoglitazone 1.5 mg was associated with statistically superior glycaemic control to pioglitazone 45 mg, while rivoglitazone 1.0 mg was non-inferior; the safety profiles of the two drugs appeared similar.


Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin/drug effects , Hypoglycemic Agents/pharmacology , Thiazolidinediones/pharmacology , Biomarkers, Pharmacological , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Europe/epidemiology , Female , Follow-Up Studies , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/administration & dosage , India/epidemiology , Lipid Metabolism/drug effects , Male , Middle Aged , Pioglitazone , Single-Blind Method , South Africa/epidemiology , Thiazolidinediones/administration & dosage , Treatment Outcome , United States/epidemiology
10.
Diabet Med ; 29(9): 1115-8, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22288732

ABSTRACT

AIMS: The aim of this study was to investigate the vascular effects of liraglutide in patients well controlled on metformin monotherapy. METHODS: Forty-four patients with Type 2 diabetes were included in the study. Main inclusion criteria were: pretreatment with metformin on a stable dosage, HbA(1c) < 53 mmol/mol (7.0%), age 30-65 years. Patients were randomized to receive additional liraglutide or to remain on metformin monotherapy. After 6 weeks (1.2 mg) and after 12 weeks (1.8 mg), venous blood was taken for the measurement of several laboratory markers characterizing vascular and endothelial function. In addition, retinal microvascular endothelial function and arterial stiffness were measured. RESULTS: HbA(1c) levels declined from 45 ± 4 mmol/mol (6.3 ± 0.4%; mean ± SD) to 40 ± 3 mmol/mol (5.8 ± 0.3%) during liraglutide treatment. Asymmetric dimethylarginin was reduced by liraglutide treatment from 0.39 ± 0.08 to 0.35 ± 0.06 µmol/l, E-selectin from 43.6 ± 15.4 to 40.8 ± 15.1 ng/ml, plasminogen activator inhibitor 1 from 861.6 ± 584.3 to 666.1 ± 499.4 ng/ml and intact proinsulin from 9.0 ± 7.2 to 7.0 ± 4.8 pmol/l at 12 weeks of treatment. The microvascular response to flicker light increased from 7.0 ± 15.1 to 15.4 ± 11.5% after 6 weeks and to 11.1 ± 9.9% after 12 weeks. No change could be observed for high-sensitivity C-reactive protein, monocyte chemotactic protein 1, vascular cell adhesion molecule or arterial stiffness parameters. CONCLUSIONS: In patients with Type 2 diabetes, well controlled with metformin monotherapy, addition of liraglutide improves several cardiovascular risk markers beyond glycaemic control.


Subject(s)
Arginine/analogs & derivatives , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , E-Selectin/blood , Glucagon-Like Peptide 1/analogs & derivatives , Metformin/therapeutic use , Plasminogen Activator Inhibitor 1/blood , Proinsulin/blood , Adult , Aged , Arginine/blood , Biomarkers/blood , Blood Glucose/metabolism , Drug Therapy, Combination , Endothelium, Vascular/physiopathology , Female , Glucagon-Like Peptide 1/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Liraglutide , Male , Microcirculation/physiology , Middle Aged , Prospective Studies
11.
J Endocrinol Invest ; 35(6): 573-9, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21791969

ABSTRACT

BACKGROUND AND AIM: Patients with multiple endocrine neoplasia type 1 (MEN1) often have low bone mineral density (BMD) attributed to primary hyperparathyroidism (pHPT). However, in MEN1 patients, other endocrine dysfunctions and conditions such as hypercortisolism, hypogonadism, and GH deficiency due to pituitary manifestation, and surgery on the upper gastrointestinal tract may affect BMD. SUBJECTS AND METHODS: In 23 patients with MEN1 (10 females, 13 males; 46±12 yr), BMD was determined by quantitative computed tomography at the forearm (pqCT), compared to a reference population and related to different conditions suspected to affect bone metabolism in MEN1. RESULTS: In this cohort, Z-score for trabecular BMD was -0.85±1.18 and for total BMD -1.16±1.04. There was a similar trend towards lower BMD in uncontrolled hyperparathyroidism, hypercortisolism, hypogonadism/GH deficiency and the state after surgery at the upper gastrointestinal tract. CONCLUSIONS: These data while confirming previous observations on reduced BMD in patients with MEN1, however, challenge its only or even predominant association with pHPT. Other conditions such as hypercortisolism, somatotrophic/ gonadotrophic pituitary insufficiency, and previous upper gastrointestinal surgery seem to be factors contributing to the risk of developing osteoporosis.


Subject(s)
Bone Density , Hyperparathyroidism, Primary/etiology , Multiple Endocrine Neoplasia Type 1/complications , Adult , Aged , Female , Humans , Hyperparathyroidism, Primary/pathology , Hyperparathyroidism, Primary/surgery , Male , Middle Aged , Multiple Endocrine Neoplasia Type 1/pathology , Multiple Endocrine Neoplasia Type 1/surgery , Prognosis , Young Adult
12.
Diabetes Obes Metab ; 13(6): 567-76, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21342412

ABSTRACT

AIM: To assess the efficacy and safety of saxagliptin + metformin initial combination therapy compared with saxagliptin or metformin alone over 76 weeks (24-week short-term + 52-week long-term extension) in treatment-naÏve type 2 diabetes mellitus patients with inadequate glycaemic control. METHODS: In this phase 3, parallel-group, double-blind, active-controlled study, 1306 patients 18-77 years of age (HbA1c 8.0-12.0%) were randomized to saxagliptin 5 mg + 500 mg metformin, saxagliptin 10 mg + 500 mg metformin, saxagliptin 10 mg + placebo or 500 mg metformin + placebo. Blinded metformin was titrated during weeks 1-5 of the short-term treatment period in 500 mg/day increments to 2000 mg/day maximum in the metformin-based treatment groups. No titration of metformin was permitted during the long-term treatment period. A total of 888 patients completed the study (76 weeks), 613 without being rescued. Changes in HbA1c, fasting plasma glucose, 120-min postprandial glucose (PPG) and PPG-area under the curve (AUC) from baseline to week 76 were analysed using a repeated-measures model. RESULTS: At 76 weeks, adjusted mean changes from baseline HbA1c (95% CI) for saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin, saxagliptin 10 mg and metformin were -2.31 (-2.44, -2.18), -2.33 (-2.46, -2.20), -1.55 (-1.70, -1.40) and -1.79% (-1.93, -1.65), respectively (post hoc and nominal p < 0.0001 vs. metformin and saxagliptin monotherapies for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin). The proportions of patients requiring rescue or discontinuation for insufficient glycaemic control were lower for saxagliptin + metformin than for either monotherapy. Little or no attenuation in PPG-AUC or 120-min PPG was observed between weeks 24 and 76 for saxagliptin + metformin, indicating persistent efficacy. Adverse event rates were similar across groups; hypoglycaemic events occurred at a low frequency. CONCLUSION: Saxagliptin + metformin initial combination therapy was well tolerated and produced sustained glycaemic control for up to 76 weeks, with greater improvements in glycaemic parameters compared with either drug alone.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptides/therapeutic use , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Adamantane/therapeutic use , Adolescent , Adult , Aged , Blood Glucose , Diabetes Mellitus, Type 2/physiopathology , Double-Blind Method , Drug Therapy, Combination , Female , Glycated Hemoglobin/drug effects , Humans , Male , Middle Aged , Treatment Outcome , Young Adult
13.
Clin Lab ; 56(7-8): 311-8, 2010.
Article in English | MEDLINE | ID: mdl-20857895

ABSTRACT

BACKGROUND: Drug degradation in the human organism is driven by detoxification mechanisms that can be affected in their efficiency by genetic mutations. The purpose of this pilot investigation was to investigate whether Type 2 diabetes is associated with mutations in prominent members of the CYP 450 isoenzyme family. METHODS: Genomic DNA was isolated from EDTA blood samples of 203 Caucasian subjects (101 patients with Type 2 diabetes and 102 non-diabetic subjects, age (mean +/- STD): 49 +/- 16 years) was analyzed. Genomic DNA was isolated from EDTA blood. Mutation analysis for CYP2C8 (*2/*3/*4), CYP2C9 (*2/*3), CYP2C19 (*2/*3), CYP2D6 (*3/*4/*5/*6) and PPARgamma (P12A) was performed by means of real-time PCR methods (Light-Cycler, Roche Diagnostics, Indianapolis, IN, USA). RESULTS: The genotyping revealed the following allele frequency distributions for the two investigated groups: CYP2C8: *2 (type 2 diabetes 3% vs. 1%, n.s.), *3 (16% vs. 3%, n.s.), *4 (15% vs. 2%, p < 0.05), CYP2C9: *2 (20% vs. 24%, n.s.), *3 (22% vs. 21%, n.s.), CYP2C19: *2 (23% s. 33%, n.s.), *3 (0% vs. 0%, n.s.), CYP2D6: *3 (3% vs. 4%, n.s.), *4 (40% vs. 37%, n.s.), *5 (3% vs. 2%, n.s.), *6 (0% vs. 0%, n.s.), PPARgamma P12A (15% vs. 21%, n.s.), i.e. all but one mutation (CYP2C8*4) were found with equal prevalence in the two cohorts. CONCLUSIONS: In this pilot investigation, we found an increased prevalence of the CYP2C8*4 mutation in the Type 2 diabetic patient group. This may result in a modification of drug degradation and drug efficacy in these patients and may have an influence, e.g. on the choice of anti-diabetic drugs. However, further trials are necessary in order to confirm our findings.


Subject(s)
Cytochrome P-450 Enzyme System/genetics , Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , Cross-Sectional Studies , Cytochrome P-450 Enzyme System/blood , DNA Mutational Analysis , Diabetes Mellitus, Type 2/blood , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , PPAR gamma/blood , PPAR gamma/genetics , Pilot Projects
14.
Diabetes Obes Metab ; 12(5): 437-41, 2010 May.
Article in English | MEDLINE | ID: mdl-20415692

ABSTRACT

AIM: Postprandial release of intact proinsulin (IP) is an independent marker for beta-cell dysfunction in patients with type 2 diabetes. This open-label, parallel-group, two-arm, pilot study compared the beta-cell protective effect of adding insulin glargine (GLA) vs. NPH insulin to ongoing metformin. MATERIAL AND METHODS: Overall, 28 insulin-naive type 2 diabetes subjects (mean +/- SD age, 61.5 +/- 6.7 years; diabetes duration, 9.8 +/- 6.5 years; HbA1c, 7.1 +/- 0.5%; BMI, 30.7 +/- 4.3 kg/m(2)) treated with metformin and sulfonylurea were randomized to add once-daily GLA or NPH at bedtime. At baseline and after 3 months, subjects received a standardized breakfast, lunch and dinner, with pre- and postprandial blood sampling to measure plasma IP, total insulin and blood glucose (BG). RESULTS: Insulin dose after 3 months was comparable in both groups (GLA vs. NPH: 23.6 +/- 13.4 vs. 23.3 +/- 12.7; p = NS ). Both treatments significantly reduced fasting BG levels (GLA: 158 +/- 19 to 121 +/- 23 mg/dl; NPH: 156 +/- 34 to 119 +/- 29 mg/dl; both p < 0.01 vs. baseline). Fasting and postprandial BG levels did not differ between groups. IP levels decreased in both groups (p < 0.05 at all timepoints). Although IP release after breakfast did not differ between treatments, GLA induced a greater reduction in IP release after lunch (p = 0.08) and dinner (p = 0.04). Total plasma insulin levels did not differ between groups. CONCLUSIONS: Adding basal insulin to metformin reduces postprandial beta-cell load. While GLA and NPH had comparable effects at breakfast, GLA reduces beta-cell stress more effectively at dinner, and with a trend at lunch, most probably because of its longer lasting pharmacodynamic profile.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/administration & dosage , Insulin, Isophane/administration & dosage , Insulin-Secreting Cells/drug effects , Insulin/analogs & derivatives , Metformin/administration & dosage , Drug Administration Schedule , Drug Therapy, Combination , Fasting , Female , Glycated Hemoglobin/drug effects , Humans , Hypoglycemic Agents/pharmacology , Insulin/administration & dosage , Insulin/pharmacology , Insulin Glargine , Insulin, Isophane/pharmacology , Insulin, Long-Acting , Insulin-Secreting Cells/metabolism , Male , Metformin/pharmacology , Middle Aged , Pilot Projects , Postprandial Period
15.
Int J Clin Pract Suppl ; (164): 11-4, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19751454

ABSTRACT

AIMS: Many patients with type 2 diabetes will ultimately need insulin therapy to maintain their target for glycaemic control. This review considers how best to achieve the target for glycaemic control in primary care. METHODS: Literature review and workshop discussions among participants at the Insulin Intensification Summit. RESULTS: Treatment aimed at reducing postprandial glucose is more effective in improving glycaemic control near target levels. Adding prandial doses of a short-acting insulin is superior to switching to a twice-daily premixed insulin. Short-acting analogue insulins offer advantages over animal insulins for intensification of basal insulin therapy, which can be achieved either by sequentially adding prandial doses or immediate introduction of three-times daily prandial dose. Each approach has benefits depending on the health care system and can be supported in primary care by a simple algorithm. CONCLUSION: Intensification of basal insulin therapy is most effectively achieved by adding a prandial short-acting insulin analogue, using a simple clinical algorithm. The regimen should be selected according to local needs.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Algorithms , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Humans , Postprandial Period/physiology
16.
Diabetes Obes Metab ; 11(6): 611-22, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19515181

ABSTRACT

AIM: The study aim was to evaluate the efficacy and safety of initial combination therapy with saxagliptin + metformin vs. saxagliptin or metformin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycaemic control. METHODS: In this multicentre, randomized, double-blind, active-controlled phase 3 trial, 1306 treatment-naïve patients with T2D >or=18 to or=8 to or=1.0 ng/ml, body mass index

Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptides/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Adamantane/administration & dosage , Adamantane/therapeutic use , Adult , Blood Glucose , Dipeptides/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Double-Blind Method , Drug Therapy, Combination/methods , Fasting , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/administration & dosage , Male , Metformin/administration & dosage , Middle Aged , Postprandial Period , Treatment Outcome
17.
Diabetes Obes Metab ; 11(5): 464-71, 2009 May.
Article in English | MEDLINE | ID: mdl-19422402

ABSTRACT

AIM: Insulin treatment is considered to be the final option for patients with progressive type 2 diabetes. This study investigated, whether reconverting type 2 patients from insulin treatment to oral treatment using pioglitazone is possible without deterioration of blood glucose control. METHODS: The PioSwitch study was a prospective, open label, proof of concept study. Thiazolidinedione-naïve patients with residual beta-cell function were switched from an existing insulin therapy to treatment with pioglitazone and glimepiride for 6 months. Efficacy was assessed by laboratory parameters and scores for evaluation of metabolic control, beta-cell function, insulin resistance and cardiovascular risk. RESULTS: In total, 98 patients [66 men, 32 women, age (mean +/- s.d.): 59 +/- 9 years; disease duration: 5.6 +/- 3.6 years; Hemoglobin A1c (HbA1c): 6.9 +/- 0.8%; body mass index (BMI): 33.9 +/- 5.2 kg/m(2), initial daily insulin therapy dose: 0.36 +/- 0.3 U/kg body weight] out of 117 screened patients were treated. During the observation period, 23 patients were prematurely terminated because of an increase in HbA1c from baseline > 0.5% or other reasons. In 75 patients (76%), no deterioration of glucose metabolism occurred and additional improvements were seen in the majority of the observation parameters [baseline vs. endpoint; HbA1c: 6.79 +/- 0.74%/6.66 +/- 0.69% (p < 0.05), glucose: 6.4 +/- 1.5/5.2 +/- 1.4 mmol/l (p < 0.001), adiponectin: 7 +/- 3 mg/l/17 +/- 8 mg/l (p < 0.001), C-peptide: 987 +/- 493/1756 +/- 789 (p < 0.001), sensitivity index derived from the intravenous glucose tolerance test (SI(ivGTT)): 1.21 +/- 0.85/1.49 +/- 0.95 (p < 0.05), hsCRP: 3.3 +/- 2.4/2.6 +/- 2.4 mg/l (p < 0.01), macrophage chemo-attractant protein 1 (MCP1): 487 +/- 246/382 +/- 295 ng/l (p < 0.05)]. BMI increased from 33.8 +/- 5.1 to 34.4 +/- 5.3 kg/m(2) (p < 0.001). CONCLUSIONS: The switch from insulin therapy resulting in a moderately HbA1c level, to oral treatment with pioglitazone was successful in a majority of patients with sufficient residual beta-cell function. It allows a simple and less expensive therapy with a better cardiovascular risk marker profile.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Adult , Aged , Biomarkers/blood , Blood Glucose/metabolism , Body Mass Index , Female , Humans , Male , Middle Aged , Pilot Projects , Pioglitazone , Prospective Studies , Sulfonylurea Compounds , Thiazolidinediones , Treatment Outcome
18.
Horm Metab Res ; 41(2): 123-31, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19214922

ABSTRACT

The metabolic syndrome is associated with an excess of increase in cardiovascular complications. Disturbances in insulin efficacy and insulin secretion are major features of the metabolic syndrome and might precede the development of diabetes mellitus by decades. Recent investigations highlighted the link between disturbances in insulin physiology and subsequent mechanisms of atherosclerosis. Insulin resistance is an early feature of increasing visceral adipose tissue and is directly associated to the activation of a couple of atherogenic pathways, including inflammation and the activation of the mitogen-activated proteinkinase pathway accelerating the atherogenic process. In patients with normal beta-cell function, insulin resistance is compensated by increased insulin release from the beta cells to keep blood glucose levels compensated. In those patients, genetically predisposed to type 2 diabetes, beta-cell function deteriorates with the development of timely, qualitative and quantitative insulin secretion disorders, and the development of overt diabetes mellitus. The coexistence of insulin resistance with functional beta cell failure results in loss of blood glucose control especially after a meal and increases the cardiovascular risk of these patients far beyond the increased glucose levels.


Subject(s)
Cardiovascular Diseases/etiology , Diabetes Mellitus, Type 2/metabolism , Insulin/metabolism , Metabolic Syndrome/metabolism , Blood Glucose , Cardiovascular Diseases/metabolism , Diabetes Mellitus, Type 2/complications , Humans , Insulin Resistance , Insulin Secretion , Insulin-Secreting Cells/metabolism , Metabolic Syndrome/complications
19.
Horm Metab Res ; 41(3): 202-6, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19224430

ABSTRACT

Retinol binding protein 4 (RBP4) has recently been suggested as a good biomarker for insulin resistance and the metabolic syndrome. With this study, we wanted to investigate the effect of pioglitazone (PIO) and simvastatin (SIMVA) on insulin resistance and RBP4 plasma concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications. The prospective, parallel, randomized, double-blind clinical trial was performed with 125 nondiabetic patients with increased cardiovascular risk (78 females, 47 males, age (mean+/-STD): 58.6+/-7.8 years, BMI: 30.8+/-4.2 kg/m (2)). They were randomized to either receive PIO (45 mg)+placebo, SIMVA (40 mg)+placebo, or PIO+SIMVA for 3 months. Key outcome measures were the HOMA (IR)-Score, an oral glucose tolerance test, adiponectin, hsCRP, and RBP4 at baseline and endpoint. No correlation could be detected between the HOMA (IR) values or the impaired fasting glucose tolerance status and RBP-4. Treatment with PIO alone or in combination with SIMVA resulted in a significant improvement of the HOMA (IR)-Score and the adiponectin values, while no change in HOMA (IR) and a decrease in adiponectin (p<0.05) were observed with SIMVA monotherapy. Reductions of hsCRP were seen in all three treatment arms (p<0.001). No changes of the plasma RBP4 concentrations were observed in any of the treatment groups (PIO: 35.6+/-7.2/36.3+/-8.7 ng/ml, PIO+SIMVA: 36.5+/-10.8/36.5+/-8 ng/ml, SIMVA: 36.1+/-8.1/36.6+/-11.1 ng/ml, all n.s. vs. baseline). Despite a partial or comprehensive improvement in insulin resistance and/or cardiovascular risk indicators in all treatment arms, no change in RBP4-levels could be observed. The regulation of RBP4 expression and secretion occurs through biochemical pathways independent from those influenced by pioglitazone or simvastatin.


Subject(s)
Cardiovascular Physiological Phenomena/drug effects , Diabetes Mellitus/physiopathology , Hypoglycemic Agents/pharmacology , Insulin Resistance/physiology , PPAR gamma/pharmacology , Retinol-Binding Proteins, Plasma/metabolism , Simvastatin/pharmacology , Thiazolidinediones/pharmacology , Cardiovascular Diseases/epidemiology , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Double-Blind Method , Gene Expression Regulation/drug effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pioglitazone , Reference Values , Retinol-Binding Proteins, Plasma/drug effects , Retinol-Binding Proteins, Plasma/genetics
20.
Clin Lab ; 54(7-8): 237-41, 2008.
Article in English | MEDLINE | ID: mdl-18942491

ABSTRACT

Visfatin is a recently described new adipokine that is considered to bind to the insulin receptor and induce insulin action via signal transduction pathways distinct from those of insulin. This study investigated whether circulating plasma visfatin levels may be influenced by PPARy activation, as shown for adiponectin and other adipokines. Samples from a prospective single-blinded placebo-controlled three-month intervention study with rosiglitazone were retrospectively analysed. The samples were derived from 39 patients with type 2 diabetes mellitus suffering from coronary artery disease as confirmed by angiography (rosiglitazone arm: 18 men, 1 woman, age (mean +/- STD): 65 +/- 9 years, disease duration: 4.8 +/- 4.0 years, HbA1c: 7.3 +/- 1.3%; Placebo: 19 men, 1 woman, age: 64 +/- 10 years, disease duration: 5.1 +/- 6.5 years, HbA1c: 7.5 +/- 1.5%). Laboratory measurements for lipids, adiponectin, and visfatin were performed with validated tests. The baseline values were comparable for all observation markers. After three months, a significant increase in the adiponectin concentrations could be observed only in the rosiglitazone group (from: 6.9 +/- 0.9 mg/l to 16.5 +/- 1.5 mg/l, (p < 0.001) vs placebo: 7.8 +/- 6.3 mg/l to 8.0 +/- 0.8 mg/l, (n.s.), p < 0.001 between the groups at endpoint). No changes were seen in both treatment arms for the other observation parameters. In particular, no influence of rosiglitazone was seen on the visfatin concentrations (25.9 +/- 2.3 ng/ml to 25.8 +/- 1.9 ng/ml; Placbo: 26.9 +/- 5.4 ng/ml to 27.2 +/- 4.9 ng/ml, n.s.). Our investigation demonstrates that rosiglitazone has different effects on circulating concentrations of adiponectin and visfatin. Visfatin secretion is not regulated by PPARgamma and further research is required to investigate its role in insulin resistance.


Subject(s)
Coronary Artery Disease/blood , Cytokines/blood , Diabetes Mellitus, Type 2/blood , Hypoglycemic Agents/pharmacology , Nicotinamide Phosphoribosyltransferase/blood , Thiazolidinediones/pharmacology , Adiponectin/blood , Aged , Female , Humans , Male , Middle Aged , PPAR gamma/agonists , PPAR gamma/metabolism , Retrospective Studies , Rosiglitazone
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