ABSTRACT
The aim of the present study was to compare the long-term safety and efficacy of insulin degludec with those of insulin glargine in patients with advanced type 2 diabetes (T2D) over 78 weeks (the 52-week main trial and a 26-week extension). Patients were randomized to once-daily insulin degludec or insulin glargine, with mealtime insulin aspart ± metformin ± pioglitazone, and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l (70-88 mg/dl). After 78 weeks, the overall rate of hypoglycaemia was 24% lower (p = 0.011) and the rate of nocturnal hypoglycaemia was 31% lower (p = 0.016) with insulin degludec in the extension trial set, while both groups of patients achieved similar glycaemic control. Rates of adverse events and total insulin doses were similar for both groups in the safety analysis set. During 18 months of treatment, insulin degludec + mealtime insulin aspart ± oral antidiabetic drugs in patients with T2D improves glycaemic control similarly, but confers lower risks of overall and nocturnal hypoglycaemia than with insulin glargine treatment.
Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin/drug effects , Hypoglycemia/prevention & control , Hypoglycemic Agents/administration & dosage , Insulin, Long-Acting/administration & dosage , Diabetes Mellitus, Type 2/blood , Drug Administration Schedule , Drug Therapy, Combination , Humans , Hypoglycemia/chemically induced , Hypoglycemic Agents/adverse effects , Insulin, Long-Acting/adverse effects , Treatment OutcomeSubject(s)
Diabetes Mellitus/epidemiology , Erectile Dysfunction/epidemiology , Self Disclosure , Adult , Age Factors , Aged , Case-Control Studies , Cerebrovascular Disorders/epidemiology , Comorbidity , Erectile Dysfunction/diagnosis , Follicle Stimulating Hormone/blood , Humans , Hypogonadism/blood , Hypogonadism/epidemiology , Ireland , Luteinizing Hormone/blood , Male , Mass Screening , Medical History Taking , Middle Aged , Prevalence , Reflex, Abnormal , Renal Insufficiency/epidemiology , Testosterone/bloodABSTRACT
Summary: A patient treated with intramuscular testosterone replacement therapy for primary hypogonadism developed blurred vision shortly after receiving his testosterone injection. The symptom resolved over subsequent weeks and recurred after his next injection. A diagnosis of central serous chorioretinopathy (CSR) was confirmed following ophthalmology review. A decision was made to change the patient's testosterone regime from this 12-weekly intramuscular injection to a daily topical testosterone gel, given the possibility that peak blood levels of testosterone following intramuscular injection were causing his ocular complaint. His CSR did not recur after this change in treatment. CSR secondary to testosterone therapy is a rare finding but has been reported previously in the literature. Learning Points: Blurred vision in patients treated with testosterone replacement therapy (TRT) should prompt an ophthalmology review. The potential for reduced risk of central serous chorioretinopathy (CSR) with daily transdermal testosterone remains a matter of conjecture. CSR is a rare potential side effect of TRT.
ABSTRACT
SUMMARY: We present three cases of acute diabetic neuropathy and highlight a potentially underappreciated link between tightening of glycaemic control and acute neuropathies in patients with diabetes. Case 1: A 56-year-old male with poorly controlled type 2 diabetes (T2DM) was commenced on basal-bolus insulin. He presented 6 weeks later with a diffuse painful sensory neuropathy and postural hypotension. He was diagnosed with treatment-induced neuropathy (TIN, insulin neuritis) and obtained symptomatic relief from pregabalin. Case 2: A 67-year-old male with T2DM and chronic hyperglycaemia presented with left lower limb pain, weakness and weight loss shortly after achieving target glycaemia with oral anti-hyperglycaemics. Neurological examination and neuro-electrophysiological studies suggested diabetic lumbosacral radiculo-plexus neuropathy (DLPRN, diabetic amyotrophy). Pain and weakness resolved over time. Case 3: A 58-year-old male was admitted with blurred vision diplopia and complete ptosis of the right eye, with intact pupillary reflexes, shortly after intensification of glucose-lowering treatment with an SGLT2 inhibitor as adjunct to metformin. He was diagnosed with a pupil-sparing third nerve palsy secondary to diabetic mononeuritis which improved over time. While all three acute neuropathies have been previously well described, all are rare and require a high index of clinical suspicion as they are essentially a diagnosis of exclusion. Interestingly, all three of our cases are linked by the development of acute neuropathy following a significant improvement in glycaemic control. This phenomenon is well described in TIN, but not previously highlighted in other acute neuropathies. LEARNING POINTS: A link between acute tightening of glycaemic control and acute neuropathies has not been well described in literature. Clinicians caring for patients with diabetes who develop otherwise unexplained neurologic symptoms following a tightening of glycaemic control should consider the possibility of an acute diabetic neuropathy. Early recognition of these neuropathies can obviate the need for detailed and expensive investigations and allow for early institution of appropriate pain-relieving medications.
ABSTRACT
This report is part of the overall evaluation of using vildagliptin in the treatment of type 2 diabetes. Here the results of a multi-center, double-blind, randomized, active-controlled study designed to compare the efficacy and safety of two years of monotherapy with vildagliptin 50 mg bid and gliclazide up to 320 mg/day in drug-naïve patients with type 2 diabetes are reported. A total of 546 patients were randomized and approximately 74% of patients completed the study in each group. HbA (1c) values were slightly higher in the gliclazide group (HbA (1c) of 8.7+/-0.1% vs. 8.5+/-0.1% in the vildagliptin group). The mean reduction in HbA (1c) from baseline to Week 104 was -0.5% in the vildagliptin group and -0.6% in the gliclazide group. The associated 95% confidence interval (CI) for the between-group difference (0.13%) in mean change was (-0.06%, 0.33%). Thus, noninferiority based on an upper limit of the CI of 0.3% was not met. In the vildagliptin group, weight increased by 0.8+/-0.2 kg compared to 1.6+/-0.2 kg in the gliclazide group (p<0.01). Mild hypoglycemia was recorded in 0.7% of patients in the vildagliptin group and in 1.7% in the gliclazide group. Both drugs were well tolerated. In summary, vildagliptin monotherapy resulted in improved glycemic control in drug-naïve patients with type 2 diabetes. Although the hypothesis of noninferiority to gliclazide was not borne out statistically, the reductions in HbA (1c) were similar over a two year period and vildagliptin had significant benefits in terms of less weight gain and less hypoglycemia.
Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Gliclazide/adverse effects , Gliclazide/therapeutic use , Nitriles/adverse effects , Nitriles/therapeutic use , Pyrrolidines/adverse effects , Pyrrolidines/therapeutic use , Adamantane/adverse effects , Adamantane/therapeutic use , Demography , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Time Factors , Treatment Outcome , VildagliptinABSTRACT
AIM: The aim of this study was to evaluate the safety and efficacy of insulin detemir in type 2 diabetes patients previously receiving NPH insulin (NPH group, n = 175) or insulin glargine (glargine group, n = 118) in combination with oral antidiabetic drugs (OADs). METHODS: Patients were transferred to insulin detemir, while the OAD regimen and number of injections remained the same. The incidence of serious adverse drug reactions, including major hypoglycaemia, and haemoglobin A(1c) (HbA(1c)), fasting glucose, within-patient fasting glucose variability and body weight change were measured at 14 weeks. RESULTS: Glycaemic control improved in both NPH (HbA(1c) = -0.2%, p < 0.05; fasting glucose -1.0 mmol/l, p < 0.0001) and glargine (HbA(1c) = -0.6%, p < 0.0001; fasting glucose -1.4 mmol/l, p < 0.0001) groups, including a reduction in fasting glucose variability (p < 0.01 for both). The incidence of total and nocturnal hypoglycaemia was reduced in both NPH and glargine groups. The incidence of major hypoglycaemia was low and did not change significantly during the follow-up period. Mean body weight was significantly reduced in the NPH (-0.7 kg, p < 0.01) and glargine (-0.5 kg, p < 0.05) groups. CONCLUSIONS: These results indicate that in type 2 diabetes, transferring from other basal insulins to insulin detemir in combination with OADs was associated with improvements in glycaemic control, which were accompanied by a reduced risk of hypoglycaemia and a reduction in body weight.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/analogs & derivatives , Administration, Oral , Blood Glucose/analysis , Blood Glucose/drug effects , Diabetes Mellitus, Type 2/metabolism , Drug Administration Schedule , Female , Glycated Hemoglobin/analysis , Humans , Hypoglycemia/prevention & control , Insulin/metabolism , Insulin/therapeutic use , Insulin Detemir , Insulin Glargine , Insulin, Long-Acting , Male , Middle Aged , Treatment Outcome , Weight GainABSTRACT
BACKGROUND: The PREDICTIVE study is a multinational observational study designed to follow up patients with diabetes who started insulin detemir (IDet) in routine care. Recruitment started in June 2004 and is ongoing in some countries. METHODS: We report 12-week follow-up data for patients with type 1 (T1D) or type 2 diabetes (T2D) in the European cohort who, as part of basal-bolus therapy, switched from once- (qd) or twice-daily (bid) neutral protamine Hagedorn insulin (NPH) to qd IDet. End-points - evaluated from patients' records and diaries - were incidence of serious adverse drug reactions, glycaemic parameters, hypoglycaemia and weight change. RESULTS: A total of 3637 patients were included, n = 1500 T1D [mean age 40.9 years, body mass index (BMI) 25.0 kg/m(2), glycosylated haemoglobin (HbA(1c)) 7.9%] and n = 2137 T2D (mean age 60.5 years, BMI 31.9 kg/m(2), HbA(1c) 8.0%). IDet was well tolerated. Lower overall, major and nocturnal rates of hypoglycaemia were observed in T1D and T2D patients switching from NPH to IDet (overall, T1D: 38.2-18.56 episodes/patient year, p < 0.001; T2D: 13.8-3.3 [corrected] episodes/patient year, p < 0.001). Switching from bid NPH to qd IDet resulted in significant 12-week reductions in HbA(1c) (T1D: -0.40%; T2D: -0.56%; both p < 0.001). Switching from qd NPH to qd IDet, resulted in HbA(1c) reductions of: T1D -0.52%; T2D -0.56%; both p < 0.001. Fasting blood glucose levels were also significantly reduced in patients with T1D or T2D. Overall mean weight changes were: T1D: 0.0 kg, T2D: -0.2 kg after 12 weeks. CONCLUSION: In routine care, patients with T1D or T2D may be switched from NPH to IDet qd as part of a basal-bolus regimen.
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin, Isophane/therapeutic use , Insulin/analogs & derivatives , Adult , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/metabolism , Fasting , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemia/etiology , Insulin/administration & dosage , Insulin Detemir , Insulin, Long-Acting , Male , Middle Aged , Prospective StudiesABSTRACT
OBJECTIVE: Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation (PREDICTIVE) is a multi-national, open-label, prospective, observational study assessing the safety and efficacy of insulin detemir in clinical practice. This post hoc subanalysis evaluates insulin-naïve patients on oral antidiabetic drugs (OADs) who were initiated on insulin detemir as basal therapy (+/- OADs). METHODS: The European cohort of the PREDICTIVE study currently includes 20,531 patients (12,981 with type 2 diabetes) who were prescribed insulin detemir and followed up for 12, 26 or 52 weeks. Here, we report data from a subgroup of 2377 OAD-treated, insulin-naïve type 2 diabetes patients for a mean follow-up of 14.4 weeks. Patients were prescribed insulin detemir as basal therapy (+/- OADs) by their physician, as part of routine clinical care. Results were reported in comparison with baseline observations. RESULTS: One serious adverse drug reaction was reported, which was a major hypoglycaemic episode. Treatment with insulin detemir (+/- OADs) significantly reduced mean haemoglobin A(1c) (HbA(1c)) (-1.3%; p < 0.0001), fasting glucose (-3.7 mmol/l; p < 0.0001), and within-patient fasting glucose variability (-0.5 mmol/l; p < 0.0001). In the majority of patients (82%), these improvements in glycaemic control were achieved with once daily administration of insulin detemir. There was a small reduction in mean body weight (-0.7 kg; p < 0.0001), which was most apparent in patients with a higher body mass index (BMI) at baseline. A significant negative relationship between weight change and baseline BMI was observed (greater the BMI, greater the weight reduction). Multiple regression analysis showed that BMI and HbA(1c) at baseline, and change in HbA(1c), were all predictors for weight change (p < 0.0001 for all), with BMI being the strongest predictor. CONCLUSIONS: Patients with type 2 diabetes naïve to insulin can be effectively treated with once-daily insulin detemir (+/- OADs) to achieve improved glycaemic control with no adverse effect on weight and a low risk of hypoglycaemia. These short-term results are consistent with the findings of clinical trials.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/analogs & derivatives , Cohort Studies , Female , Humans , Insulin/therapeutic use , Insulin Detemir , Insulin, Long-Acting , Male , Middle Aged , Prospective StudiesABSTRACT
We have investigated the antidiabetic action of troglitazone in aP2/DTA mice, whose white and brown fat was virtually eliminated by fat-specific expression of diphtheria toxin A chain. aP2/DTA mice had markedly suppressed serum leptin levels and were hyperphagic, but did not gain excess weight. aP2/DTA mice fed a control diet were hyperlipidemic, hyperglycemic, and had hyperinsulinemia indicative of insulin-resistant diabetes. Treatment with troglitazone alleviated the hyperglycemia, normalized the tolerance to intraperitoneally injected glucose, and significantly decreased elevated insulin levels. Troglitazone also markedly decreased the serum levels of cholesterol, triglycerides, and free fatty acids both in wild-type and aP2/DTA mice. The decrease in serum triglycerides in aP2/DTA mice was due to a marked reduction in VLDL- and LDL-associated triglyceride. In skeletal muscle, triglyceride levels were decreased in aP2/DTA mice compared with controls, but glycogen levels were increased. Troglitazone treatment decreased skeletal muscle, but not hepatic triglyceride and increased hepatic and muscle glycogen content in wild-type mice. Troglitazone decreased muscle glycogen content in aP2/DTA mice without affecting muscle triglyceride levels. The levels of peroxisomal proliferator-activated receptor gamma mRNA in liver increased slightly in aP2/DTA mice and were not changed by troglitazone treatment. The results demonstrate that insulin resistance and diabetes can occur in animals without significant adipose deposits. Furthermore, troglitazone can alter glucose and lipid metabolism independent of its effects on adipose tissue.
Subject(s)
Adipose Tissue/physiology , Chromans/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacology , Thiazoles/pharmacology , Thiazolidinediones , Animals , Blood Glucose/metabolism , Body Weight , Cholesterol/metabolism , Eating , Fatty Acids/metabolism , Glycogen/metabolism , Insulin/metabolism , Insulin Resistance , Insulin Secretion , Leptin , Lipoproteins, LDL/metabolism , Lipoproteins, VLDL/metabolism , Mice , Mice, Transgenic , Organ Size , Proteins/metabolism , Receptors, Cytoplasmic and Nuclear/biosynthesis , Receptors, Cytoplasmic and Nuclear/genetics , Transcription Factors/biosynthesis , Transcription Factors/genetics , Triglycerides/metabolism , TroglitazoneABSTRACT
Mutations in the gene for the transcription factor hepatocyte nuclear factor (HNF) 1alpha cause maturity-onset diabetes of the young (MODY) 3, a form of diabetes that results from defects in insulin secretion. Since the nature of these defects has not been defined, we compared insulin secretory function in heterozygous [HNF-1alpha (+/-)] or homozygous [HNF-1alpha (-/-)] mice with null mutations in the HNF-1alpha gene with their wild-type littermates [HNF-1alpha (+/+)]. Blood glucose concentrations were similar in HNF-1alpha (+/+) and (+/-) mice (7.8+/-0.2 and 7.9+/-0.3 mM), but were significantly higher in the HNF-1alpha (-/-) mice (13.1+/-0.7 mM, P < 0.001). Insulin secretory responses to glucose and arginine in the perfused pancreas and perifused islets from HNF-1alpha (-/-) mice were < 15% of the values in the other two groups and were associated with similar reductions in intracellular Ca2+ responses. These defects were not due to a decrease in glucokinase or insulin gene transcription. beta cell mass adjusted for body weight was not reduced in the (-/-) animals, although pancreatic insulin content adjusted for pancreas weight was slightly lower (0.06+/-0.01 vs. 0.10+/-0.01 microg/mg, P < 0.01) than in the (+/+) animals. In summary, a null mutation in the HNF-1alpha gene in homozygous mice leads to diabetes due to alterations in the pathways that regulate beta cell responses to secretagogues including glucose and arginine. These results provide further evidence in support of a key role for HNF-1alpha in the maintenance of normal beta cell function.
Subject(s)
DNA-Binding Proteins , Diabetes Mellitus, Type 2/physiopathology , Insulin/metabolism , Nuclear Proteins , Transcription Factors/physiology , Animals , Arginine/pharmacology , Blood Glucose/analysis , Body Weight , Calcium/analysis , Gene Expression Regulation/genetics , Glucose/pharmacology , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Heterozygote , Homozygote , Immunohistochemistry , Insulin Secretion , Islets of Langerhans/chemistry , Islets of Langerhans/physiopathology , Mice , Mice, Knockout , Organ Size , Pancreas/pathology , Pancreas/physiopathology , RNA, Messenger/analysis , Transcription Factors/geneticsABSTRACT
BACKGROUND: Anaemia is an increasingly recognised entity in patients with diabetes mellitus. AIMS: We aimed to determine the prevalence of anaemia in our population of patients with diabetes, and to examine the factors associated with anaemia. METHODS: The haemoglobin (Hb) levels in a consecutive series of patients attending for annual review of their diabetes over a three-month period were measured. Patients were classified as anaemic as per the WHO criteria. RESULTS: During the period of study, 270 patients attended for review. Eleven per cent of males and 16% of females were anaemic. Seventy four per cent of anaemic patients had a serum creatinine <110micromol/l and 72% of anaemic patients had a calculated creatinine clearance of >60ml/min. CONCLUSIONS: Anaemia was relatively common in patients attending for routine outpatient diabetes clinic review. The high prevalence of anaemia supports the routine screening for anaemia in the diabetes out-patient clinic, including in those without overt nephropathy.
Subject(s)
Anemia/epidemiology , Anemia/etiology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Cluster Analysis , Female , Humans , Ireland/epidemiology , Male , Mass Screening , Middle AgedABSTRACT
To determine whether loss of beta-cell mass and function in the NOD mouse occurs gradually, beginning after the onset of insulitis, or abruptly, just before the onset of overt diabetes, beta-cell mass and rates of beta-cell proliferation and insulin secretory responses from the perfused pancreas were measured in NOD and control NOD/Scid mice at 8-9, 13, and 18 weeks of age. Of the NOD mice, 11 and 70% had diabetes (fasting blood glucose >8.3 mmol/l) at 13 and 18 weeks of age, respectively. Beta-cell mass in 8-week-old NOD mice was 69% of control mice (P>0.05), but the rate of 5-bromo-2-deoxyuridine uptake was greater, suggesting a compensatory proliferative response to ongoing autoimmune beta-cell destruction. Despite an increase in the rate of beta-cell proliferation, beta-cell mass was significantly reduced by 42% in 13-week-old nondiabetic NOD mice and by 73% in 18-week-old diabetic NOD mice. Insulin secretory responses to glucose and arginine demonstrated reductions of similar magnitude. In 18-week-old diabetic NOD mice, insulin secretion was reduced to a greater degree than beta-cell mass, suggesting the presence of beta-cell dysfunction in addition to reduced mass. These results suggest that in the NOD mouse, beta-cell destruction begins soon after the onset of insulitis. Despite a compensatory beta-cell proliferative response, beta-cell mass progressively falls and is significantly reduced by 13 weeks despite normal blood glucose concentrations. Diabetes may be present when residual beta-cell mass represents 30% of control levels.
Subject(s)
Cell Division , Diabetes Mellitus, Type 1/pathology , Islets of Langerhans/pathology , Aging , Animals , Arginine/pharmacology , Blood Glucose/metabolism , Body Weight , Female , Glucose/pharmacology , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/metabolism , Mice , Mice, Inbred NODABSTRACT
The present study was undertaken to test the hypothesis that exposure to high glucose concentrations enhances insulin secretion in pancreatic islets from glucokinase-deficient mice. Insulin secretion and intracellular calcium ([Ca2+]i) were measured as the glucose concentration was increased from 2 to 26 mmol/l in islets from heterozygous glucokinase (GK)-deficient mice (GK+/-) and their wild-type littermates (GK+/+). Results obtained in islets incubated in 11.6 or 30 mmol/l glucose for 48-96 h were compared. GK+/- islets that had been incubated in 30 mmol/l glucose showed improved although not normal insulin secretory and [Ca2+]i responses to the standard glucose challenge as well as an enhanced ability to sense small amplitude glucose oscillations. These effects were associated with increased glucokinase activity and protein. In contrast, exposure of GK+/+ islets to 30 mmol/l glucose increased their basal insulin secretion but reduced their incremental secretory responses to glucose and their ability to detect small amplitude glucose oscillations. Thus exposure of GK+/- islets to 30 mmol/l glucose for 48-96 h enhanced their ability to sense and respond to a glucose stimulus, whereas similar exposure of GK+/+ islets induced evidence of beta-cell dysfunction. These findings provide a mechanistic framework for understanding why glucokinase diabetes results in mild hyperglycemia that tends not to increase over time. In addition, the absence of one allele of the glucokinase gene appears to protect against glucose-induced beta-cell dysfunction (glucose toxicity).
Subject(s)
Glucokinase/genetics , Hyperglycemia/physiopathology , Insulin/metabolism , Animals , Blood Glucose/metabolism , Body Weight , Calcium/metabolism , Dose-Response Relationship, Drug , Glucokinase/drug effects , Glucokinase/metabolism , Glucose/administration & dosage , Glucose/pharmacology , Glucose Tolerance Test , Insulin Secretion , Islets of Langerhans/cytology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Mice , MutationABSTRACT
Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.
Subject(s)
Calpain/physiology , Insulin/physiology , Leucine/analogs & derivatives , Adipocytes/metabolism , Animals , Calcium/physiology , Calpain/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Deoxyglucose/pharmacokinetics , Electric Conductivity , Glucose/metabolism , In Vitro Techniques , Insulin/metabolism , Insulin/pharmacology , Insulin Secretion , Intracellular Membranes/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Islets of Langerhans/physiology , Leucine/pharmacology , Mice , Mice, Inbred C57BL , Muscle, Skeletal/metabolism , NADP/metabolism , Oligopeptides/pharmacology , Osmolar Concentration , Time FactorsABSTRACT
BACKGROUND: Resistance to Thyroid Hormone (RTH) is a condition caused by tissue hyposensitivity to the effects of circulating thyroid hormone, and may be misdiagnosed as hyperthyroidism. AIMS: We report the first case of RTH in an Irish patient highlighting the clinical features and the pathophysiological mechanism underlying the characteristic laboratory abnormalities found in the condition. METHODS: We describe an isolated case of RTH initially misdiagnosed as hyperthyroidism, and detail the investigations which ultimately led to the correct diagnosis. Genetic screening of the thyroid hormone receptor beta gene was performed. RESULTS: Thyroid function tests including T3 suppression test and TRH-stimulation test suggested a diagnosis of RTH. Genetic testing failed to demonstrate a mutation in the thyroid hormone receptor. CONCLUSION: RTH is a rare inherited condition that may be misdiagnosed as hyperthyroidism. The case we describe most likely results from a de novo mutation in an as yet undiscovered gene. RTH should be considered in patients with elevated thyroid hormone levels and normal TSH so that unnecessary and potentially harmful treatment can be avoided.
Subject(s)
Hyperthyroidism/diagnosis , Pituitary Neoplasms/diagnosis , Thyroid Hormone Receptors beta/genetics , Thyroid Hormone Resistance Syndrome/diagnosis , Adult , DNA Mutational Analysis , Diagnosis, Differential , Female , Humans , Magnetic Resonance Imaging , Mutation , Risk Assessment , Severity of Illness Index , Thyroid Function Tests , Thyroid Hormone Resistance Syndrome/genetics , Thyroid Hormones/metabolismABSTRACT
This study investigates the mechanisms responsible for glucagon-like peptide-1 (GLP-1)-induced insulin secretion in Zucker diabetic fatty (ZDF) rats and their lean control (ZLC) littermates. Glucose, and 100 nmol/L GLP-1 (7-37 hydroxide) in the presence of stimulatory glucose concentrations, induced insulin secretion in islets from ZLC animals. In contrast, ZDF islets hypersecreted insulin at low glucose (5 mmol/L) and were poorly responsive to 15 mmol/L glucose stimulation, but increased insulin secretion following exposure to GLP-1. The insulin secretory response to 100 nmol/L GLP-1 was reduced by 88% in ZLC islets exposed to exendin 9-39. The intracellular Ca2+ concentration ([Ca2+]i) increased in fura-2-loaded ZLC islets following stimulation with 12 mmol/L glucose alone or GLP-1 in the presence of 12 mmol/L glucose. The increases in [Ca2+]i and insulin secretion in ZLC islets induced by GLP-1 were attenuated by 1 micromol/L nitrendipine. In contrast, neither glucose nor GLP-1 substantially increased [Ca2+]i in ZDF islets. Furthermore, insulin secretory responses to GLP-1 were not significantly inhibited in ZDF islets by nitrendipine. However, the insulin secretory response to GLP-1 in both ZLC and ZDF islets was ablated by cholera toxin. Our findings indicate that in ZLC islets, GLP-1 induces insulin secretion by a mechanism that depends on Ca2+ influx through voltage-dependent Ca2+ channels, whereas in ZDF islets, the action of GLP-1 is mediated by Ca2+-independent signaling pathways.
Subject(s)
Calcium/physiology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus/metabolism , Glucagon/pharmacology , Insulin/metabolism , Islets of Langerhans/metabolism , Obesity , Peptide Fragments/pharmacology , Protein Precursors/pharmacology , Rats, Zucker/metabolism , Animals , Glucagon-Like Peptide 1 , Insulin Secretion , RatsABSTRACT
To determine if serum leptin levels are affected by thyroid dysfunction, we measured its concentration in serum samples from 25 euthyroid controls and 25 subjects each with hypothyroidism and thyrotoxicosis collected over a 3-month period. Mean leptin levels in the euthyroid (24.1 +/- 8.3 microg/L), hypothyroid (22.7 +/- 7.0 microg/L) and thyrotoxic (23.3 +/- 4.3 microg/L) groups were not significantly different. Data were available to express leptin in terms of body mass index (BMI) in 11 euthyroid, and 6 untreated hypothyroid and thyrotoxic individuals. There was a significant positive correlation between BMI and leptin level (r = 0.60, p = .0002) for this subgroup, irrespective of their thyroid status. These data suggest that leptin levels are not affected by thyroid dysfunction.
Subject(s)
Proteins/metabolism , Thyroid Diseases/physiopathology , Female , Humans , Hypothyroidism/blood , Hypothyroidism/physiopathology , Leptin , Male , Middle Aged , Thyroid Diseases/blood , Thyroid Function Tests , Thyrotoxicosis/blood , Thyrotoxicosis/physiopathology , Thyrotropin/blood , Thyroxine/bloodABSTRACT
BACKGROUND: Target blood pressure control in patients with type 2 diabetes should be 130/85 mmHg or less; however, it is not clear how achievable this target is in clinical practice. AIM: To assess the adequacy of blood pressure control in patients with type 2 diabetes attending a busy outpatient clinic. METHODS: One hundred and eight patients with type 2 diabetes were assessed for the presence of hypertension using a cut-off value of 130/85 mmHg. Antihypertensive treatment and diabetic complications were evaluated. RESULTS: Hypertension was present in 67% of patients, in whom 90% were receiving anti-hypertensive treatment. Forty-nine per cent of the treated patients achieved target blood pressure. Of the undertreated patients, 55% were on one antihypertensive agent, 30% were on two agents and 15% were on three or more agents. The corresponding figures for the adequately treated patients were 28%, 31% and 41%, respectively (p=0.03). CONCLUSION: Adequate blood pressure control was underachieved in this patient group underlying the difficulty in treating blood pressure to target values in patients with type 2 diabetes in the setting of outpatient diabetes clinics. A more aggressive strategy, in particular the use of multiple antihypertensive agents should be adopted.
Subject(s)
Diabetes Mellitus, Type 2/complications , Hypertension/epidemiology , Ambulatory Care Facilities , Blood Pressure Determination , Chi-Square Distribution , Female , Humans , Hypertension/etiology , Hypertension/prevention & control , Male , PrevalenceABSTRACT
BACKGROUND: Acromegaly secondary to growth hormone releasing hormone (GHRH) secretion is exceptionally rare. AIM: To report a case of acromegaly diagnosed in 1984 and assumed to be pituitary in origin. Sixteen years later, the cause was found to be a GHRH secreting neuroendocrine pancreatic tumour. METHOD: A case report. CONCLUSION: Although ectopic GHRH production is very rare, endocrinologists should be aware of this possibility in acromegaly patients if a pituitary tumour was not detected using pituitary imaging.