David Jesudason

Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D insufficiency

It is known that nursing-home patients with vitamin D insufficiency have elevated serum parathyroid hormone (PTH) as well as raised serum alkaline phosphatase (ALP). Although it is well known that vitamin D insufficiency and secondary hyperparathyroidism are common among the elderly in western countries, there is continuing controversy over the level of serum 25-hydroxyvitamin D [25(OH)D] necessary for bone health. We approached this issue by examining the relationships between serum 25(OH)D, ionized calcium, PTH, and ALP and the urinary bone resorption markers hydroxyproline, pyridinoline, and deoxypyridinoline, corrected for creatinine (OHPr/Cr, Pyd/Cr, and Dpd/Cr, respectively), in 486 postmenopausal women of mean age 63 (SD 9.5) years, who were referred to our osteoporosis and menopause clinics for investigation. When the patients were divided into two groups with 25(OH)D above and below 20 nmol/L, 30 nmol/L, 40 nmol/L, 50 nmol/L, 60 nmol/L, or 70 nmol/L, the most significant differences between the two groups thus derived was found at a serum 25(OH)D level of 60 nmol/L (P < 0.001 for all markers). The most significant difference between groups for serum PTH was found when the patients were divided at a serum 25(OH)D of 50 nmol/L. PTH, OHPr/Cr, Pyd/Cr, and ALP were inversely related to serum 25(OH)D. PTH was inversely related to serum ionized calcium. There was a trend for ionized calcium to be positively related to 25(OH)D, but this did not reach statistical significance. We conclude that rises in three bone resorption markers and ALP can be detected in postmenopausal women when the serum 25(OH)D level falls below 60 nmol/L. Levels above this may be required for optimal bone health.

The interaction between dietary protein and bone health

The role of dietary protein in bone health has been controversial. On the one hand, a plentiful supply of dietary amino acids has been considered important to support bone remodeling while on the other hand there have been concerns that the dietary acid load associated with protein consumption promotes hypercalciuria and loss of bone calcium stores. This article reviews the effect of dietary protein on bone mass and bone density, and the effect on markers of bone resorption and formation and also on fracture risk, looking at both cross-sectional and longitudinal studies and examining both meat and vegetable protein including soy and milk basic protein. The results are not entirely consistent and suggest that the interaction between dietary protein and other components in a mixed diet, such as calcium intake and vegetables and fruit to neutralize acid, are important and may determine whether high-protein diets are beneficial to bone health. Overall the results suggest that dietary protein has a modest beneficial effect on bone markers and bone density. This effect has yet to be consistently linked to reduced fracture risk, probably because of the role of other etiological factors such as the risk of falls. There is not enough evidence currently to suggest that animal protein is superior or inferior to vegetable protein, or that milk or soy protein, respectively, is more favorable than other protein sources.

Weight-loss diets in people with type 2 diabetes and renal disease: a randomized controlled trial of the effect of different dietary protein amounts

BACKGROUND Higher-protein weight-loss diets (defined as >25% of energy as protein) are not recommended for individuals with type 2 diabetes because of their potential adverse effect on renal function. OBJECTIVE We aimed to examine the effect of such diets on renal function over 12 mo in people with type 2 diabetes and early renal disease. DESIGN Overweight and obese people with type 2 diabetes were screened to identify those with an albumin:creatinine ratio from 3 to 30 mg/mmol. Seventy-six subjects were randomly assigned to either a moderate-protein weight-loss diet or a standard-protein weight-loss diet for 12 mo. The primary endpoint was the change in renal function as assessed by the isotope glomerular filtration rate (GFR), estimated GFR, and cystatin C. Forty-five subjects (moderate protein: n = 21; standard protein: n = 24) completed the study. RESULTS The mean (±SE) weight loss was not different between diets at 9.7 ± 13.4 kg for the moderate-protein diet and 6.6 ± 7.1 kg for the standard-protein diet. There were no changes in renal function or albuminuria or blood pressure, although glycated hemoglobin was lowered with both diets. Changes in renal function were related to the baseline estimated GFR. Patients with stage 1-3 renal disease (<120 mL · min(-1) · 1.73 m(-2); n = 33) had an improvement in renal function, whereas patients with hyperfiltration (>120 mL · min(-1) · 1.73 m(-2); n = 12) had a decrease in the GFR. After adjustment for weight loss, the baseline GFR remained a significant predictor of outcomes with no effect of dietary treatment. An average difference in protein intake between diets of 19 ± 6 g/d was achieved. CONCLUSION Weight loss improved renal function, but differences in dietary protein had no effect. This trial was registered at the Australian and New Zealand Clinical Trial Register as ACTRN12608000045314.

Endocannabinoid system in food intake and metabolic regulation

Purpose of review As the incidence of obesity and the metabolic syndrome has increased, research has focused on the importance of the endocannabinoid system in the brain and peripheral tissues. Rimonabant, an inverse agonist of the CB1 receptor is being used therapeutically. This review presents recent advances in endocannabinoid physiology. Recent findings The endocannabinoid system interacts with other anorexigenic and orexigenic pathways to regulate food intake in the hypothalamus, and the hedonistic value of food in the mesolimbic system. Endocannabinoid system overactivity contributes to hepatic steatosis, increased adipose tissue inflammation, dysregulated insulin signalling in the pancreas and disturbed oxidative pathways in skeletal muscle. The breakdown pathways for anandamide and 2-arachidonoylglycerol, the endocannabinoid receptor ligands, are reviewed, and the recent discoveries of endocannabinoid receptor polymorphisms and their relationship to obesity and metabolic disease noted. The favourable effect of rimonabant on fat mass glycaemic control, lipid metabolism and overall cardiovascular risk must be tempered by adverse effects on mood. Summary The ubiquitous role of the endocannabinoid system in food intake and energy metabolism is now established. Drugs that manipulate different aspects of this system may benefit subjects with the metabolic and cachectic syndromes.

Sustained effects of a protein ‘preload’ on glycaemia and gastric emptying over 4 weeks in patients with type 2 diabetes: A randomized clinical trial

We have shown that the capacity of 25g whey preloads to slow gastric emptying and reduce postprandial glycaemia persists after 4 weeks regular exposure in patients with diet-controlled type 2 diabetes. This dietary strategy therefore appears feasible for larger clinical trials to evaluate beneficial effects on long-term glycaemic control. Registered with the Australian New Zealand Clinical Trials Registry: ACTRN12614000831684.

Interpreting different measures of glomerular filtration rate in obesity and weight loss: pitfalls for the clinician

To combat the increasing incidence of obesity, much research has been devoted to devising successful strategies for weight loss, including manipulation of diet and gastric surgery. Obesity itself can be associated with renal dysfunction, and the degree of reversibility of this with weight loss has being studied. However, there are significant limitations and flaws in the methods we have available to measure glomerular filtration rate (GFR) in overweight and obese subjects. Obesity is associated with changes in body composition including lean and fat mass. This has implications for assumptions that underpin creatinine-based measures such as creatinine clearance, estimated GFR and other equations devised for obesity including the Salazar–Corcoran equation. These changes in body composition also affect measures of glomerular filtration such as cystatin C and nuclear medicine isotope scans. This article will review the accuracy of these current measures of renal function in the obese and consider the evidence for adjusting for body surface area or adjusting for lean body mass. Finally, the effect of weight loss itself on serial measurements of renal function in a given individual, independent of a true change in renal function, will be reviewed. Ultimately using the Cockcroft–Gault equation with an adjustment for lean body mass seems to be the best measure for renal function in obesity. No method for measuring renal function in situations of weight loss has been shown to be unequivocally superior.

Comparison of 2 weight-loss diets of different protein content on bone health: a randomized trial

BACKGROUND It has been hypothesized that hip-fracture rates are higher in developed than in developing countries because high-protein (HP) Western diets induce metabolic acidosis and hypercalciuria. Confounders include interactions between dietary protein and calcium, sodium, and potassium. OBJECTIVE We determined whether an HP or a high-normal-protein (HNP) weight-loss diet caused greater loss in bone mineral density (BMD) over 24 mo. DESIGN The Weight Loss, Protein and Bone Density Study was conducted from 2008 to 2011 in 323 overweight [body mass index (BMI; in kg/m(2)) >27] postmenopausal women, with a total hip BMD t score less than -2.0. Subjects were randomly assigned to receive an isocaloric calcium-replete HP (≥90 g protein/d) or HNP (<80 g protein/d) weight-loss diet, with the aim of a difference of 20 g protein/d. A total of 186 subjects (90 subjects in the HP group, 96 subjects in the HNP group) completed 12 mo, and 137 subjects (69 subjects in the HP group, 68 subjects in the HNP group) completed 24 mo. RESULTS Biomarkers confirmed a difference in protein intake of 16 and 13.1 g at 12 and 24 mo, respectively. Mean (±SE) weight loss was equal; HP subjects lost 7.9 ± 0.9 kg and HNP subjects lost 8.9 ± 0.9 kg at 24 mo. Subjects lost 1-2% BMD annually at lumbar spine vertebrae 2-4, the forearm, the femoral neck, and hip. ANCOVA showed no effect of the HP or HNP diet (P > 0.05 for diet and diet-time interactions). A diet-by-time analysis showed that the HNP diet increased C-terminal telopeptide and osteocalcin (P ≤ 0.001 for each) despite hypercalciuria (P = 0.029). CONCLUSION High dietary protein intake during weight loss has no clinically significant effect on bone density but slows bone turnover. This trial was registered at the Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au) as ACTRN12608000229370.

High protein weight loss diets in obese subjects with type 2 diabetes mellitus

BACKGROUND AND AIM Diets where carbohydrate has been partially exchanged for protein have shown beneficial changes in persons with type 2 diabetes but no studies have enrolled people with albuminuria. We aim to determine if a high protein to carbohydrate ratio (HPD) in an energy reduced diet has a beneficial effect on metabolic control and cardiovascular risk factors without negatively affecting renal function. METHOD AND RESULTS Adult, overweight participants with type 2 diabetes, with albuminuria (30-600 mg/24 h or an albumin-to-creatinine ratio of 3.0-60 mg/mmol), and estimated GFR of >40 ml/min/1.73 m(2) were enrolled. Participants were randomized to an HPD or an SPD. Protein:fat:carbohydrate ratio was 30:30:40% of energy for the HPD and 20:30:50% for the SPD. Main outcomes were renal function, weight loss, blood pressure, serum lipids and glycaemic control. We recruited 76 volunteers and 45 (35 men and 10 women) finished. There were no overall changes in renal function at 12 months and no significant differences in weight loss between groups (9.7 ± 2.9 kg and 6.6 ± 1.4 kg HPD and SPD group respectively; p = 0.32). Fasting blood glucose decreased significantly with no treatment effect. The decrease in HbA1c differed between treatments at 6 months (HPD -0.9 vs. SPD -0.3%; p = 0.039) but not at 12 months. HDL increased significantly with no treatment effects. There were no changes in LDL or blood pressure overall but DBP was lower in the HPD group (p = 0.024) at 12 months. CONCLUSION Weight loss improved overall metabolic control in this group of well controlled participants with type 2 diabetes regardless of diet composition.

SGLT2 Inhibitor–Associated Euglycemic Diabetic Ketoacidosis: A South Australian Clinical Case Series and Australian Spontaneous Adverse Event Notifications

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been linked with diabetic ketoacidosis (DKA) (1–4). However, characteristics of “at-risk” patients are less well described. Clinical cases were collected from South Australia between December 2015 and March 2017. The audit was approved by the Royal Adelaide Hospital Human Research Ethics Committee (HREC reference no. HREC/17/RAH/185). The Therapeutic Goods Administration (TGA) of the Australian Government Department of Health was contacted, and a search of the Database of Adverse Event Notifications (medicines) for all reports of SGLT2 inhibitor–associated DKA was requested up until April 2017 using the search terms ketoacidosis, diabetic ketoacidosis, and generic and brand drug names. Full case line listings for each notification were provided by the TGA. Autoantibodies against glutamic acid decarboxylase (GAD) and insulinoma-associated antigen 2 (tyrosine phosphatase IA-2) were quantitated using commercial ELISA test kits (Euroimmun AG, Lubeck, Germany). These assays are calibrated in international units (IU) using the first World Health Organization reference reagent for islet cell antibodies (1999, reagent 97/550; National Institute for Biological Standards and Control, Hertfordshire, U.K.), which contains 100 IU of anti-GAD and 100 IU of anti–IA-2 per ampoule by definition. We identified thirteen cases of SGLT2 inhibitor–associated DKA occurring in South Australia between December 2015 and March 2017 (Table 1). Eight case subjects had type 2 diabetes (T2D) and five had …

Utility of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equations in Obese Diabetic Individuals Before and After Weight Loss

To the Editor: Obese individuals with type 2 diabetes with albuminuria can have normal or elevated (hyperfiltration) glomerular filtration rates (GFRs). In this group, traditional creatinine-based GFR estimating equations fare badly compared to measured GFR (mGFR) using gold-standard radioisotope methods. Their higher fat-free mass can increase creatinine production compared with lighter individuals with the same mGFR. Following weight loss, the utility of eGFR equations to determine changes in mGFR is unclear in the presence of altered body composition and loss of lean mass. Moreover, in the obese, the pitfalls of indexing GFR to a body surface area (BSA) of 1.73 m are well known. The CKD-EPI creatinine equation and subsequent CKD-EPI equations incorporating cystatin C and both cystatin C and creatinine are increasingly used. We hypothesized that the cystatin C equations may be superior in obese cohorts with normal or elevated GFRs as well as after weight loss because cystatin C is not affected by muscle mass. The Weight Loss, Protein and Renal Health Study was a randomized clinical trial comparing moderate and standard dietary protein weight loss regimens in terms of kidney function over 12 months in overweight participants with type 2 diabetes and albuminuria. The main results recently were published. In this study, mean weight loss did not differ between diets, at 9.7 6 13.4 (SE) kg for the moderate-protein diet and 6.6 6 7.1 kg for the standard-protein diet, with an average difference in protein intake between diets of 19 6 6 g/d. Dietary protein had no significant effect on eGFR, but both groups experienced changes in eGFRs during the period of weight loss. Patients with baseline eGFRs , 120 mL/min/1.73 m (n 5 33) had an improvement in eGFR, whereas patients with baseline eGFRs