Higher Waist Hip Ratio Genetic Risk Score Is Associated with Reduced Weight Loss in Patients with Severe Obesity Completing a Meal Replacement Programme.

Background: A better understanding of the influence of genetic factors on the response to lifestyle interventions in people with obesity may allow the development of more personalised, effective and efficient therapeutic strategies. We sought to determine the influence of six obesity-related genetic risk scores on the magnitude of weight lost by patients with severe obesity who completed a dietary intervention. Methods: In this single-centre prospective cohort study, participants with severe and complicated obesity who completed a 24-week, milk-based meal replacement programme were genotyped to detect the frequency of common risk alleles for obesity and type 2 diabetes-related traits. Genetic risk scores (GRS) for six of these traits were derived. Participants with a potentially deleterious monogenic gene variant were excluded from the analysis. Results: In 93 patients completing the programme who were not carrying a known obesity-related gene mutation, 35.5% had diabetes, 53.8% were female, mean age was 51.4 ± 11 years, mean body mass index was 51.5 ± 8.7 and mean total weight loss percent at 24 weeks was 16 ± 6.3%. The waist-hip ratio (WHR) GRS was inversely associated with percentage total weight loss at 24 weeks (adjusted ß for one standard deviation increase in WHR GRS -11.6 [-23.0, -0.3], p = 0.045), and patients in the lowest tertile of WHR GRS lost more weight. Conclusions: Patients with severe and complicated obesity with a genetic predisposition to central fat accumulation had less weight loss in a 24-week milk-based meal replacement programme, but there was no evidence for influence from the five other obesity-related genetic risk scores on the response to dietary restriction.

Changes in the Leptin to Adiponectin Ratio Are Proportional to Weight Loss After Meal Replacement in Adults With Severe Obesity.

Hypocaloric diets are known to induce changes in adipokine secretion, but the influence of a low energy liquid diet (LELD) on the leptin: adiponectin ratio (LAR), a measure of insulin resistance and cardiovascular risk, has not previously been investigated in patients with severe obesity. We conducted a prospective, single-center cohort study of adults with severe obesity (defined as body mass index (BMI) ≥40 kgm-2, or ≥35 kgm-2 with co-morbidities) who completed a 24-week milk-based LELD. We measured leptin, adiponectin and LAR at the start and on completion of the programme. Of 120 patients who started, 52 (43.3 %) completed the programme. Their mean age was 50.3 ± 11.2 (range 18-74) years, 29 (55.8 %) were female and 20 (38.5 %) had type 2 diabetes mellitus (T2DM). Weight decreased from 148.2 ± 39.6 to 125.4 ± 34.8 kg and BMI decreased from 52.4 ± 11.1 to 44.3 ± 9.8 kgm-2, respectively (all p < 0.001). In patients with T2DM, HbA1c decreased from 60.0 ± 17.4 to 47.5 ± 15.5 mmol/mol (p < 0.001). Leptin decreased (from 87.2 [48.6, 132.7] to 39.1 [21.0, 76.4] ng/ml) and adiponectin increased (from 5.6 [4.5, 7.5] to 7.1 [5.5, 8.5] µg/ml), with a reduction in LAR from 15 [8.4, 22.4] to 5.7 [3.0, 9.1] ng/µg (all p < 0.001), indicating decreased insulin resistance. The percentage weight lost was associated with the percentage reduction in LAR (ß = 2.9 [1.7, 4.1], p < 0.001) and this association was stronger in patients with T2DM. Patients with severe obesity who completed a milk-based LELD had a substantial reduction in LAR, consistent with decreased insulin resistance and cardiovascular risk, proportional to weight loss.

HIST1H1E syndrome with type 2 diabetes.

A 20-year-old woman was referred to the diabetes clinic with type 2 diabetes diagnosed at the age of 19. Her body mass index was 31.4 kg/m2, HbA1C was 76 mmol/mol, GAD antibodies were negative with a detectable C-peptide. She had a characteristic facial appearance with widespread eyes, posterior hairline suggesting a facial gestalt and abnormal dentition. She also had hypothyroidism, mild intellectual disability, primary amenorrhoea and patent ductus arteriosus. Karyotyping reported normal 46XX karyotype. Genetic testing revealed a pathogenic variant in the gene encoding the HIST1H1E protein which confirmed her diagnosis of HIST1H1E syndrome. Type 2 diabetes has not been reported in previous cases of HIST1H1E and so this is the first reported case of type 2 diabetes with HIST1H1E syndrome.

Long-Term Changes in Weight in Patients With Severe and Complicated Obesity After Completion of a Milk-Based Meal Replacement Programme.

Introduction: Even with very significant short term weight loss with intensive dietary restriction, subsequent weight regain remains a challenge for most patients. We sought to assess long-term weight change in patients with obesity following completion of a 24-week milk-based meal replacement programme. Methods: We conducted a retrospective cohort study of bariatric patients who completed our milk-based meal replacement programme. This programme started with an 8-week weight loss phase, followed by weight stabilization (8 weeks) and weight maintenance (8 weeks) phases, after which patients were followed up in the bariatric outpatient clinics. A paired sample t-test was used to compare mean differences in weight at the start and the end of the programme and at follow-up. Linear regression was used to identify predictors of weight regain. Results: In total, 78 patients had long term follow-up data at a mean of 34.4 ± 19.8 months after the start of the milk diet and were included in this analysis. Mean body mass index at baseline was 50.5 ± 7.6 kg m-2, 41 (52.6%) were female and the mean age was 51.6 ± 12.0 (range 18.0-71.5) years. Weight decreased from144 ± 26 kg at the start of the milk diet to 121.2 ± 24 kg at completion (P < 0.001), with a non-significant trend upwards in the 1st and 2nd years of follow-up to 129.0 ± 27.7 (P = 0.07 compared to nadir) and 123.4 ± 29.0kg (P = 0.17), respectively. Although regains in the 3rd and 4th follow-up years were substantial to 131.0 ± 22.3 (P < 0.001), and 139.8 ± 35.4 kg (P < 0.001), there was still a moderate net weight loss of 4.7 [9.5, 0.21] and 7.0 [13.9, 0.26] kg (both P = 0.04) between the start and the 3rd and 4th follow-up years, respectively. The amount of weight regain was inversely associated with weight loss at completion of the programme, age, and directly associated with the duration of follow up in months (ß = 1.2 [0.46, 1.9] P = 0.002). Conclusion: In patients with severe obesity who completed a milk-based meal replacement programme and lost a large amount of weight, over 4 years of follow-up there was very substantial weight regain. Greater initial weight loss and older age were associated with less subsequent weight regain.

Changes in alanine aminotransferase in adults with severe and complicated obesity during a milk-based meal replacement programme.

INTRODUCTION: Excess adiposity is associated with fat accumulation within the liver, and non-alcoholic steatohepatitis (NASH) is highly prevalent in bariatric patients. Elevated alanine aminotransferase (ALT) is associated with prevalent NASH. We sought to determine the influence of a milk-based meal replacement weight-loss programme on ALT levels in adults with severe and complicated obesity. METHODS: We conducted a retrospective cohort study of patients who completed a 24-week meal replacement programme, comprised of a weight loss phase followed by weight stabilisation and maintenance phases, each 8 weeks long. ALT was quantified using an enzymatic assay with spectrophotometric detection. We examined changes over time in ALT using the non-parametric Wilcoxon singed-rank test and the Friedman test. RESULTS: Of 105 patients, 56 were female, mean age was 51.2 ± 11.2 (range 18.0-71.6) years. There was an unanticipated but transient increase in ALT from 28.0 [20.0, 40.5] iu/L at baseline to 40.0 [26.0, 55.0] iu/L after 2 weeks (p < 0.0005), followed by a gradual reduction to 21.0 [17.0, 28.3] iu/L by 24 weeks (p < 0.0005). The overall reductions in ALT were more pronounced in patients who had elevated levels at baseline. Body weight decreased from 144.2 ± 28.0 kg at baseline to 121.6 ± 25.4 kg at 24 weeks (p < 0.0005) and body mass index (BMI) decreased from 50.7 ± 8.1 kg m-2 at baseline to 43.0 ± 7.6 kg m-2 by 24 weeks (p < 0.0005). CONCLUSION: In adults with severe and complicated obesity undergoing a milk-based meal replacement programme, there was an initial unanticipated rise in ALT in the first 2 weeks, followed by a gradual overall reduction by 24 weeks. These findings suggest that rapid weight loss secondary to significant caloric restriction might induce a transient deterioration in hepatic steatosis prior to an ultimate overall improvement.

Effects of a Milk-Based Meal Replacement Program on Weight and Metabolic Characteristics in Adults with Severe Obesity.

OBJECTIVE: Low energy meal replacement regimens can induce short-term weight loss in patients with severe obesity, but usually require specially formulated dietary supplements. We sought to determine the effects of a milk-based meal replacement program on anthropometric and metabolic characteristics in adults with severe obesity. METHODS: We conducted a retrospective cohort study of patients attending our hospital-based bariatric medicine service who completed a 24-week program consisting of eight weeks of milk-based meal replacement followed by weight stabilisation and maintenance phases. Patients were seen fortnightly by the bariatric physician, nurse and dietitian. We assessed changes in anthropometric and metabolic outcomes in completers at 0, 8, 16 and 24 weeks. RESULTS: Of 105 program completers available for follow-up, 53.3% were female. Mean age was 51.1±11.2 years. Body weight decreased from 144.0±27.6 kg at baseline to 121.1±25.0 kg at 24 weeks (P<0.001), a mean total body weight loss of 15.9±6.0%, with a reduction in body mass index from 50.6±8.0 to 42.6±7.6 kg m-2 (P<0.001). In patients with diabetes, haemoglobin A1c decreased from 66.3±13.0 to 48.3±13.5 mmol/mol (P<0.001) and diabetes medication use decreased significantly. There were significant improvements also in lipid profiles and reductions in antihypertensive medication use. CONCLUSION: These preliminary findings suggest that completion of a 24-week milk-based meal replacement program has large effects on important outcomes in adults with severe obesity. However, attrition was high. Prospective assessment of the efficacy, safety, durability and cost-effectiveness of this intervention seems warranted.

Prolonged acidosis is a feature of SGLT2i-induced euglycaemic diabetic ketoacidosis.

SUMMARY: We describe two cases of SGLT2i-induced euglycaemic diabetic ketoacidosis, which took longer than we anticipated to treat despite initiation of our DKA protocol. Both patients had an unequivocal diagnosis of type 2 diabetes, had poor glycaemic control with a history of metformin intolerance and presented with relatively vague symptoms post-operatively. Neither patient had stopped their SGLT2i pre-operatively, but ought to have by current treatment guidelines. LEARNING POINTS: SGLT2i-induced EDKA is a more protracted and prolonged metabolic derangement and takes approximately twice as long to treat as hyperglycaemic ketoacidosis. Surgical patients ought to stop SGLT2i medications routinely pre-operatively and only resume them after they have made a full recovery from the operation. While the mechanistic basis for EDKA remains unclear, our observation of marked ketonuria in both patients suggests that impaired ketone excretion may not be the predominant metabolic lesion in every case. Measurement of insulin, C-Peptide, blood and urine ketones as well as glucagon and renal function at the time of initial presentation with EDKA may help to establish why this problem occurs in specific patients.

Utilising a milk-based meal replacement programme in a bariatric patient with poorly controlled type 2 diabetes mellitus.

A 45-year-old man with poorly controlled type 2 diabetes (T2DM) (HbA1c 87 mmol/mol) despite 100 units of insulin per day and severe obesity (BMI 40.2 kg/m2) was referred for bariatric intervention. He declined bariatric surgery or GLP1 agonist therapy. Initially, his glycaemic control improved with dietary modification and better adherence to insulin therapy, but he gained weight. We started a low-energy liquid diet, with 2.2 L of semi-skimmed milk (equivalent to 1012 kcal) per day for 8 weeks (along with micronutrient, salt and fibre supplementation) followed by 16 weeks of phased reintroduction of a normal diet. His insulin was stopped within a week of starting this programme, and over 6 months, he lost 20.6 kg and his HbA1c normalised. However, 1 year later, despite further weight loss, his HbA1c deteriorated dramatically, requiring introduction of linagliptin and canagliflozin, with good response. Five years after initial presentation, his BMI remains elevated but improved at 35.5 kg/m2 and his glycaemic control is excellent with a HbA1c of 50 mmol/mol and he is off insulin therapy. Whether semi-skimmed milk is a safe, effective substrate for carefully selected patients with severe obesity complicated by T2DM remains to be determined. Such patients would need frequent monitoring by an experienced multidisciplinary team. Learning points: Meal replacement programmes are an emerging therapeutic strategy to allow severely obese type 2 diabetes patients to achieve clinically impactful weight loss. Using semi-skimmed milk as a meal replacement substrate might be less costly than commercially available programmes, but is likely to require intensive multidisciplinary bariatric clinical follow-up. For severely obese adults with poor diabetes control who decline bariatric surgery or GLP1 agonist therapy, a milk-based meal replacement programme may be an option. Milk-based meal replacement in patients with insulin requiring type 2 diabetes causes rapid and profound reductions in insulin requirements, so rigorous monitoring of glucose levels by patients and their clinicians is necessary. In carefully selected and adequately monitored patients, the response to oral antidiabetic medications may help to differentiate between absolute and relative insulin deficiency.

Risperidone-induced type 2 diabetes presenting with diabetic ketoacidosis.

A 28-year-old male presented with 2 days of vomiting and abdominal pain, preceded by 2 weeks of thirst, polyuria and polydipsia. He had recently started risperidone for obsessive-compulsive disorder. He reported a high dietary sugar intake and had a strong family history of type 2 diabetes mellitus (T2DM). On admission, he was tachycardic, tachypnoeic and drowsy with a Glasgow Coma Scale (GCS) of 10/15. We noted axillary acanthosis nigricans and obesity (BMI 33.2 kg/m2). Dipstick urinalysis showed ketonuria and glycosuria. Blood results were consistent with diabetic ketoacidosis (DKA), with hyperosmolar state. We initiated our DKA protocol, with intravenous insulin, fluids and potassium, and we discontinued risperidone. His obesity, family history of T2DM, acanthosis nigricans and hyperosmolar state prompted consideration of T2DM presenting with 'ketosis-prone diabetes' (KPD) rather than T1DM. Antibody markers of beta-cell autoimmunity were subsequently negative. Four weeks later, he had modified his diet and lost weight, and his metabolic parameters had normalised. We reduced his total daily insulin dose from 35 to 18 units and introduced metformin. We stopped insulin completely by week 7. At 6 months, his glucometer readings and glycated haemoglobin (HbA1c) level had normalised. LEARNING POINTS: Risperidone-induced diabetic ketoacidosis (DKA) is not synonymous with type 1 diabetes, even in young white patients and may be a manifestation of 'ketosis-prone' type 2 diabetes (KPD).KPD is often only confirmed after the initial presentation, when islet autoimmunity and cautious phasing out of insulin therapy have been assessed, and emergency DKA management remains the same.As in other cases of KPD, a family history of T2DM and presence of cutaneous markers of insulin resistance were important clinical features suggestive of an alternative aetiology for DKA.

Central pulse pressure in chronic kidney disease: a chronic renal insufficiency cohort ancillary study.

Central pulse pressure (PP) can be noninvasively derived using the radial artery tonometric methods. Knowledge of central pressure profiles has predicted cardiovascular morbidity and mortality in several populations of patients, particularly those with known coronary artery disease and those receiving dialysis. Few data exist characterizing central pressure profiles in patients with mild-moderate chronic kidney disease who are not on dialysis. We measured central PP cross-sectionally in 2531 participants in the Chronic Renal Insufficiency Cohort Study to determine correlates of the magnitude of central PP in the setting of chronic kidney disease. Tertiles of central PP were <36 mm Hg, 36 to 51 mm Hg, and >51 mm Hg with an overall mean (+/-SD) of 46+/-19 mm Hg. Multivariable regression identified the following independent correlates of central PP: age, sex, diabetes mellitus, heart rate (negatively correlated), glycosylated hemoglobin, hemoglobin, glucose, and parathyroid hormone parathyroid hormone concentrations. Additional adjustment for brachial mean arterial pressure and brachial PP showed associations for age, sex, diabetes mellitus, weight, and heart rate. Discrete intervals of brachial PP stratification showed substantial overlap within the associated central PP values. The large size of this unique chronic kidney disease cohort provides an ideal situation to study the role of brachial and central pressure measurements in kidney disease progression and cardiovascular disease incidence.

Aortic PWV in chronic kidney disease: a CRIC ancillary study.

BACKGROUND: Aortic pulse wave velocity (PWV) is a measure of arterial stiffness and has proved useful in predicting cardiovascular morbidity and mortality in several populations of patients, including the healthy elderly, hypertensives and those with end-stage renal disease receiving hemodialysis. Little data exist characterizing aortic stiffness in patients with chronic kidney disease (CKD) who are not receiving dialysis, and in particular the effect of reduced kidney function on aortic PWV. METHODS: We performed measurements of aortic PWV in a cross-sectional cohort of participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study to determine factors which predict increased aortic PWV in CKD. RESULTS: PWV measurements were obtained in 2,564 participants. The tertiles of aortic PWV (adjusted for waist circumference) were <7.7 m/s, 7.7-10.2 m/s, and >10.2 m/s with an overall mean (+/- s.d.) value of 9.48 +/- 3.03 m/s (95% confidence interval = 9.35-9.61 m/s). Multivariable regression identified significant independent positive associations of age, blood glucose concentrations, race, waist circumference, mean arterial blood pressure, gender, and presence of diabetes with aortic PWV and a significant negative association with the level of kidney function. CONCLUSIONS: The large size of this unique cohort, and the targeted enrollment of CKD participants provides an ideal situation to study the role of reduced kidney function as a determinant of arterial stiffness. Arterial stiffness may be a significant component of the enhanced cardiovascular risk associated with kidney failure.

Beta-blockers for hypertension: are they going out of style?

Although beta-blockers lower blood pressure in most patients, the outcomes of clinical hypertension trials of these drugs have been disappointing, and the value of beta-blockers in treating hypertensive patients who do not have compelling indications for them has been questioned. Until these drugs are proved beneficial, they should be used as antihypertensive therapy only in patients with compelling cardiac indications for them or as add-on agents in those with uncontrolled or resistant hypertension.

Aortic pulse pressure is associated with carotid IMT in chronic kidney disease: report from Chronic Renal Insufficiency Cohort.

BACKGROUND: Patients with chronic kidney disease (CKD) have a disproportionate risk of cardiovascular disease. This study was designed to assess the association between two noninvasive measures of cardiovascular risk, pulse wave analysis (PWA), and carotid intima-media thickness (IMT), in a cohort of CKD patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. METHODS: Three hundred and sixty-seven subjects with CKD enrolled in the CRIC study at the University of Pennsylvania site (mean age 59.9 years, blood pressure 129/74 mm Hg, estimated glomerular filtration rate 48 ml/min/1.73 m2, IMT 0.8 mm) had both carotid IMT and PWA measurements. Carotid ultrasound was also used to determine the presence of plaque. PWA was used to determine augmentation index (AI), amplification ratio (AMPR), aortic pulse pressure (C_PP), and central aortic systolic pressure (C_SP). RESULTS: IMT was significantly associated with all PWA-derived measures. However, on multivariable linear regression analysis, only AMPR (regression coefficient -0.072, P = 0.006), C_PP (regression coefficient 0.0025, P < 0.001), and C_SP (regression coefficient 0.0017, P < 0.001) remained significantly associated with IMT. The prevalence of carotid plaque in the cohort was 59%. Of the PWA-derived measures, only C_PP was significantly associated with the presence of carotid plaque (P < 0.001). CONCLUSIONS: PWA-derived measures are associated with carotid IMT and plaque in the CKD. Of these measures, C_PP was most associated with carotid IMT and plaque.

Blood pressure goals and arterial stiffness in chronic kidney disease.

The association of optimal blood pressure (BP) control and arterial stiffness was evaluated in 172 patients with chronic kidney disease. The authors compared the augmentation index (AIx) of patients who achieved a recommended BP goal (<130/80 mm Hg) with those who did not (> or = 130/80 mm Hg). The median age was 57 years, 60% were male, and 70% were Caucasian. One-third of patients had achieved a BP goal of <130/80 mm Hg. AIx was significantly lower in patients who achieved BP goal than in those who did not (median AIx, 19% vs 23%; P=.04). AIx remained significantly lower in patients who achieved the BP goal, after adjusting for age, sex, and height (mean effect on AIx, -3.3%; 95% confidence interval, -6.1% to -0.4%; P=.03). Achievement of BP goal of <130/80 mm Hg in chronic kidney disease patients is associated with significantly lower AIx and may reflect a reduction in overall arterial stiffness.

Resistant hypertension in the elderly.

Resistant hypertension is more prevalent in the elderly population. Current data clearly shows the benefit of blood pressure control in older individuals. It is important to first differentiate pseudoresistance from true resistant and institute appropriate therapy. In those patients with resistant hypertension without an identifiable cause, non invasive measurement of hemodynamic profile is an important option to achieve meet blood pressure goals.

Uric acid transport.

PURPOSE OF REVIEW: The goal of this article is to review the physiology and describe newly defined molecular mechanisms that are responsible for renal urate transport. RECENT FINDINGS: Four complementary DNAs have recently been cloned whose expressed proteins transport urate. Two of these proteins have been localized to the apical membrane of proximal tubular cells: one, a urate transporter/channel, a galectin, is an electrogenic transporter (an ion channel); the second is a urate-anion electroneutral exchanger, a member of the organic anion transporter family. The other urate transport proteins, organic anion transporters 1 and 3, are also members of the organic anion transporter family. These proteins have been localized to the basolateral membrane of proximal tubular cells: organic anion transporter 1 is an electroneutral organic anion exchanger; the mechanism of urate transport on organic anion transporter 3 remains to be determined. SUMMARY: The molecular definition and localization of four urate transport proteins provides a basis for developing a molecular model of the bi-directional transport of urate in renal proximal tubules. It seems likely that the urate-anion exchanger is responsible for luminal reabsorption while the urate transporter/channel permits secretion of urate from the cell into the lumen. Since organic anion transporters 1 and 3 reside in the basolateral membrane, one or both may be relevant in the reabsorptive flux of urate into the peritubular capillary as well as in the cellular uptake of urate from the peritubular space, the first step in the process of urate secretion. Knowledge of the molecular basis of urate transport should provide greater insights into states of altered transport as well as assist in development of drugs to modify urate flux.