Geoffrey Braatvedt

Effects of improved glycaemic control on endothelial function in patients with type 2 diabetes

Background: Patients with type 2 diabetes have abnormal endothelial function but it is not certain whether improvements in glycaemic control will improve endothelial function.

A community-based model of care improves blood pressure control and delays progression of proteinuria, left ventricular hypertrophy and diastolic dysfunction in Māori and Pacific patients with type 2 diabetes and chronic kidney disease: a randomized controlled trial

BACKGROUND In this study, our main goal was to determine whether an integrated, community-based model of care using culturally appropriate health-care assistants to manage hypertension in Māori and Pacific patients with diabetes and chronic kidney disease (CKD) is more effective than conventional care in achieving blood pressure (BP) targets and delaying progression of cardiac and renal end-organ damage. METHODS Sixty-five Māori and Pacific patients (aged 47-75 years) with type 2 diabetes, moderate CKD (>0.5 g proteinuria/day, serum creatinine 130-300 µmol/l) and hypertension were randomized to usual care (n = 32) or community/intervention care (n = 33) for 12 months. Community care patients were visited monthly by a nurse-led health-care assistant for BP measurement. Antihypertensives were adjusted using a stepwise protocol, aiming for a BP <130/80 mmHg. Office BP and renal and echocardiographic parameters were measured at baseline and 12 months. RESULTS Baseline characteristics including office BP, renal and echocardiographic parameters, and number of antihypertensives were well matched in both groups. By 12 months, the community care patients had achieved a significantly greater reduction in office systolic BP (-21 ± 26 mmHg vs -12 ± 20 mmHg, P = 0.04) and in 24-h urine protein (-1.4 ± 2.6 g vs +0.1 ± 2.8 g, P = 0.04). The number of prescribed antihypertensives was greater in these patients at 12 months (3.4 ± 1.1 vs 2.3 ± 1.0, P < 0.01). Left ventricular (LV) mass and left atrial (LA) volume progressed in the usual care group, but not in the intervention group (P < 0.05). CONCLUSION This novel model of care is more effective than conventional care in lowering systolic BP and reducing cardiac and renal end-organ damage in these high-risk patients.

The effects of intensive glycaemic control on body composition in patients with type 2 diabetes

SUMMARY

A Novel Point Mutation of the Human Glucocorticoid Receptor Gene Causes Primary Generalized Glucocorticoid Resistance Through Impaired Interaction With the LXXLL Motif of the p160 Coactivators: Dissociation of the Transactivating and Transreppressive Activities

CONTEXT Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. The molecular basis of the condition has been ascribed to inactivating mutations in the human glucocorticoid receptor (hGR) gene. OBJECTIVE The objective of the study was to present three new cases caused by a novel mutation in the hGR gene and to delineate the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. DESIGN AND RESULTS The index case (father) and his two daughters presented with increased urinary free cortisol excretion and resistance of the hypothalamic-pituitary-adrenal axis to dexamethasone suppression in the absence of clinical manifestations suggestive of Cushing syndrome. All subjects harbored a novel, heterozygous, point mutation (T→G) at nucleotide position 1724 of the hGR gene, which resulted in substitution of valine by glycine at amino acid 575 of the receptor. Compared with the wild-type receptor, the hGRαV575G demonstrated a significant (33%) reduction in its ability to transactivate the mouse mammary tumor virus promoter in response to dexamethasone, a 50% decrease in its affinity for the ligand, and a 2.5-fold delay in nuclear translocation. Although it did not exert a dominant negative effect on the wild-type receptor and preserved its ability to bind to DNA, hGRαV575G displayed significantly enhanced (∼80%) ability to transrepress the nuclear factor-κΒ signaling pathway. Finally, the mutant receptor hGRαV575G demonstrated impaired interaction with the LXXLL motif of the glucocorticoid receptor-interacting protein 1 coactivator in vitro and in computer-based structural simulation via its defective activation function-2 (AF-2) domain. CONCLUSIONS The natural mutant receptor hGRαV575G causes primary generalized glucocorticoid resistance by affecting multiple steps in the glucocorticoid signaling cascade, including the affinity for the ligand, the time required for nuclear translocation, and the interaction with the glucocorticoid-interacting protein-1 coactivator.

Peripheral Neuropathy and Tear Film Dysfunction in Type 1 Diabetes Mellitus

Purpose. To compare tear film metrics in patients with type 1 diabetes mellitus (DM) and healthy controls and investigate the association between peripheral neuropathy and ocular surface quality. Methods. Dry eye symptoms were quantified in 53 patients with type 1 DM and 40 age-matched controls. Ocular examination included tear film lipid layer thickness grading, tear film stability and quantity measurement, and retinal photography. DM individuals additionally underwent a detailed neuropathy assessment. Results. Neither mean age nor dry eye symptom scores differed significantly between the DM and control groups (P = 0.12 and P = 0.33, resp.). Tear lipid thickness (P = 0.02), stability (P < 0.0001), and quantity (P = 0.01) were significantly lower in the DM group. Corneal sensitivity was also reduced in the DM group (P < 0.001) and tear film stability was inversely associated with total neuropathy score (r = −0.29, P = 0.03). Conclusion. The DM group exhibited significantly reduced tear film stability, secretion, and lipid layer quality relative to the age-matched control group. The negative correlation between tear film parameters and total neuropathy score suggests that ocular surface abnormalities occur in parallel with diabetic peripheral neuropathy.

Impact of diabetes mellitus on the ocular surface: a review

Although diabetes mellitus is reaching epidemic proportions worldwide, ocular surface complications are still largely believed to be uncommon. Although these complications are not often sight threatening, the general well‐being of patients and the cost of their health care can be respectively compromised and added by them. Over the last decade, an association of ocular surface complications (in particular reduced corneal sub‐basal nerve density and corneal sensitivity) with peripheral neuropathy has emerged, which could help recognize the development of peripheral complications at an earlier stage and also provide research opportunities for examining new treatment modalities of diabetic neuropathies. The ocular surface complications of diabetes mellitus and their association with peripheral neuropathy are reviewed by this report.Although diabetes mellitus is reaching epidemic proportions worldwide, ocular surface complications are still largely believed to be uncommon. Although these complications are not often sight threatening, the general well-being of patients and the cost of their health care can be respectively compromised and added by them. Over the last decade, an association of ocular surface complications (in particular reduced corneal sub-basal nerve density and corneal sensitivity) with peripheral neuropathy has emerged, which could help recognize the development of peripheral complications at an earlier stage and also provide research opportunities for examining new treatment modalities of diabetic neuropathies. The ocular surface complications of diabetes mellitus and their association with peripheral neuropathy are reviewed by this report.

Angiotensin‐1‐converting enzyme and angiotensinogen gene polymorphisms in Maori and Pacific Island people in New Zealand

There is accumulating evidence to suggest that disturbances in the renin–angiotensin system at a tissue level may play a role in a number of diseases. However, reports of possible disease associations with polymorphisms of two genes in this system (angiotensin-1-converting enzyme (ACE) and angiotensinogen) are conflicting, with some studies suggesting an association with diseases such as ischaemic heart disease,1 diabetic retinopathy and nephropathy,2 while others show no apparent association.3,4

Risk factors for recurrent admissions with diabetic ketoacidosis: a case–control observational study

To perform a detailed analysis of patients with recurrent diabetic ketoacidosis admissions in order to establish risk factors for readmission.

Glucose control peri‐myocardial infarction

This review summarises the available clinical trials data investigating the effects of glucose lowering on mortality in patients admitted to hospital with acute myocardial infarction. The results of these studies are inconclusive with no clear evidence that this intervention has additional benefit over and above routine care.

Long-term effectiveness of a community-based model of care in Māori and Pacific patients with type 2 diabetes and chronic kidney disease: a 4-year follow up of the DElay Future End Stage Nephropathy due to Diabetes (DEFEND) study.

The Delay Future End Stage Nephropathy due to Diabetes study was a randomised controlled trial of Māori and Pacific patients with advanced diabetic nephropathy, comparing a community‐based model of care with usual care. The intervention group achieved lower blood pressure (BP), proteinuria and less end‐organ damage. After the intervention ended, all patients reverted to usual care, and were followed to review the sustainability of the intervention.