Diabetic foot ulcer incidence and survival with improved diabetic foot services: an 18-year study.

AIMS: To ascertain the effects of improvements in diabetic foot services over 18 years on incidence of diabetic foot ulceration. We also compared survival time from first ulcer development with presence of neuropathy, peripheral vascular disease, age and healing. METHODS: Persons with new ulceration and those at high risk of ulcer development were referred to community podiatry from 1998. Their details were recorded, with verbal consent, on a central database. The effects of neuropathy, peripheral vascular disease, healing and age on survival were analysed by Cox proportional hazards ratios. RESULTS: The incidence of first ulcer presentation decreased from 11.1 to 6.1 per 1000 persons between 2003 to 2017 (P <0.0001). Recurrent ulceration incidence remained stable. Prevalence of chronic and new foot ulceration combined increased from 20.7 to 33.1 per 1000 persons (P <0.0001). Ten-year survival was 85% for persons presenting with first ulcer and aged < 65 years, 50% for those aged 65-74 years and 25% for those aged 75-81 years (P < 0.0001). In those with peripheral vascular disease 5-year survival was 35% (P <0.001). CONCLUSIONS: Integrated care for the diabetic foot in one National Health Service (NHS) health service area over 18 years was associated with a reduction in first presentations of diabetic foot ulceration, but failed to reduce recurrent ulceration. Cumulative prevalence of all ulcers continues to increase. Monitoring ulceration incidence can inform audit and planning of diabetic foot care services. Survival is better than reported previously in persons < 65 years and in the absence of peripheral vascular disease.

Diabetes-related major lower limb amputation incidence is strongly related to diabetic foot service provision and improves with enhancement of services: peer review of the South-West of England.

AIMS: To investigate the relationship between high diabetes-related lower limb amputation incidence and foot care services in the South-West region of England. METHODS: The introduction of 10 key elements of foot care service provision in one area of the South-West resulted in stabilization of foot ulcer incidence and sustained reduction in amputation incidence from 2007. Services introduced included administrative support, standardized general practice foot screening, improved community podiatry staffing, hospital multidisciplinary foot clinics, effective care pathways, availability of an orthotist and audit. Peer reviews of the region's diabetes foot care services were undertaken to assess delivery of these service provisions and compare this with major amputation incidence in other regions with data provided by Yorkshire and Humber Public Health Observatory Hospital Episode Statistics. Recommendations were made to improve service provision. In 2015 changes in service provision and amputation incidence were reviewed. RESULTS: Initial reviews in 2013 showed that the 3-year diabetes-related major amputation incidence correlated inversely with adequate delivery of diabetes foot care services (P=0.0024, adjusted R2 =0.51). Repeat reviews in 2015 found that two or more foot care service improvements were reported by six diabetes foot care providers, with improvement in outcomes. The negative relationship between major amputation incidence and service provision remained strong both in the period 2012-2015 and in the year 2015 only (P ≤0.0012, adjusted R2 =0.56, and P= 0.0005, R2 =0.62, respectively). CONCLUSIONS: Major diabetes-related lower limb amputation incidence is significantly inversely correlated with foot care services provision. Introduction of more effective service provision resulted in significant reductions in major amputation incidence within 2 years. Failure to improve unsatisfactory service provision resulted in continued high amputation incidence.

Prediction of protective sensory loss, neuropathy and foot ulceration in type 2 diabetes.

OBJECTIVES: To prospectively determine clinical and biochemical characteristics associated with the development of peripheral neuropathy, loss of protective sensation, and foot ulceration in persons with type 2 diabetes mellitus (DM) over 7 years. RESEARCH DESIGN AND METHODS: Graded monofilament (MF) testing, vibration perception threshold, and neuropathy symptom questionnaires were undertaken in 206 participants with type 2 DM without peripheral vascular disease or history of foot ulceration and 71 healthy participants without DM at baseline and after 7 years. 6 monthly glycosylated hemoglobin (HbA1c) levels and annual serum lipid profiles were measured during follow-up of those with DM. Incident foot ulceration was recorded at follow-up. RESULTS: Taller stature and higher quartiles of serum triglyceride and HbA1c levels were associated with neuropathy at follow-up (p=0.008). Remission of baseline neuropathy was observed in 7 participants at follow-up. 9 participants with type 2 DM developed foot ulcers by the end of the study, only 1 at low risk. Mean HbA1c levels were higher in those who developed foot ulceration (p<0.0001). 1 participant with neuropathy throughout developed a Charcot foot. Failure to perceive 2 or more 2, 4 and 6 g MF stimuli at baseline predicted loss of protective sensation at follow-up. CONCLUSIONS: Tall stature and worse metabolic control were associated with progression to neuropathy. Mean HbA1c levels were higher in those who developed foot ulcers. Graded MF testing may enrich recruitment to clinical trials and assignation of high risk for foot ulceration.

Heterozygous ABCC8 mutations are a cause of MODY.

AIMS/HYPOTHESIS: The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K(ATP)) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy. METHODS: We sequenced the ABCC8 gene in 85 patients with a BMI <30 kg/m², no family history of neonatal diabetes and who were deemed sensitive to sulfonylureas by the referring clinician or were sulfonylurea-treated. All had tested negative for mutations in the HNF1A and HNF4A genes. RESULTS: ABCC8 mutations were found in seven of the 85 (8%) probands. Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified. Only four probands fulfilled MODY criteria, with two diagnosed after 25 years and one patient, who had no family history of diabetes, as a result of a proven de novo mutation. CONCLUSIONS/INTERPRETATION: ABCC8 mutations can cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY. Therefore, sequencing of ABCC8 in addition to the known MODY genes should be considered if such features are present, to facilitate optimal clinical management of these patients.

Body fat distribution, serum glucose, lipid and insulin response to meals in Alström syndrome.

BACKGROUND: Alström syndrome is an autosomal recessive condition characterized by obesity, insulin resistance and hypertriglyceridaemia. Responses to fat and carbohydrate ingestion are important in planning dietetic advice and may help to explain the mechanism of metabolic disorder in the syndrome. METHODS: After a 12-h fast, five Alström subjects received a 3.1 MJ (742 kcal), 75.8% fat breakfast on day 1, and a 3.3 MJ (794 kcal), 77.5% carbohydrate breakfast on day 2. Serum glucose, triglyceride and insulin levels were measured at baseline, and 2 and 3.5 h post-meal. Abdominal computerized tomography in three subjects and magnetic resonance imaging in one demonstrated distribution of abdominal fat. RESULTS: Body fat was distributed subcutaneously, as well as viscerally. There were no changes in serum glucose, insulin or triglycerides after the high fat meal. Triglycerides remained stable after the high carbohydrate meal but glucose and log insulin levels increased [8.4 +/- 4.1 to 13.4 +/- 6.9 mmol L(-1) (P < 0.05) and 2.6 +/- 0.27 to 3.15 +/- 0.42 pmol L(-1) (P < 0.05), respectively]. CONCLUSIONS: Dietetic advice in Alström syndrome must include calorie restriction to reduce obesity, which is predominantly subcutaneous. This study has shown that low carbohydrate advice may prove more effective than fat restriction in control of hyperglycaemia and hyperinsulinism. A single high energy meal does not exacerbate hypertriglyceridaemia.

Is arterial stiffening in Alström syndrome linked to the development of cardiomyopathy?

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive condition characterized by retinal degeneration, childhood obesity, and severe insulin resistance. Dilated cardiomyopathy of unknown aetiology is a well-recognized and potentially lethal complication. The aim of this study was to investigate the relationship between vascular function, hyperinsulinaemia and cardiac performance in AS. MATERIALS AND METHODS: Fifteen subjects with AS (mean age 21 years, range 10-35) were studied and compared with age-, sex-, and blood pressure-matched healthy controls. Large artery stiffness and wave reflections were assessed in both groups by measuring aortic and brachial pulse wave velocity (PWV) (carotid-femoral and carotid-radial) and augmentation index (AIX) (Sphygmocor). In AS subjects, left ventricular function was assessed by echocardiography and metabolic parameters including fasting insulin, glucose, lipids and brain natriuretic peptide were also measured. RESULTS: Comparing AS subjects vs. controls (mean +/- SD), AIX was elevated in AS subjects (18 +/- 9% vs. 3 +/- 11%, P < 0.0001). No significant changes in brachial PWV (8.1 +/- 1.3 m s(-1) vs. 7.3 +/- 1.1 m s(-1), P = 0.14) or aortic PWV (6.5 +/- 1.1 m s(-1) vs. 6.0 +/- 1.0 m s(-1), P = 0.26) were observed. AS subjects were hyperinsulinaemic and had disturbances in lipid profiles relative to controls. No correlations were observed between vascular, metabolic and echocardiographic parameters. CONCLUSIONS: In AS there are alterations in the shape of the central arterial pressure waveform associated with augmented aortic systolic pressure and indicative of increased wave reflection. Unfavourable central arterial haemodynamics in AS may contribute to the development of cardiomyopathy but other aetiological factors are probably involved.

Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome.

CONTEXT: Alström syndrome (AS) is a monogenic form of infancy-onset obesity and insulin resistance, caused by ALMS1 mutations. The natural history of the insulin resistance is unknown, in particular how this relates to changes in body composition. It is also unclear how ALMS1 mutations relate to the characteristic phenotype. OBJECTIVES: Our objectives were to characterize body composition and metabolic parameters, to establish ALMS1 mutation spectrum of United Kingdom AS patients, and to determine whether a genotype-phenotype correlation exists. DESIGN AND PATIENTS: We conducted a cross-sectional cohort study of 12 unrelated subjects with AS. Age-standardized body composition was assessed by anthropometry and dual-energy x-ray absorptiometry and insulin sensitivity by homeostasis model assessment. The exons and intron-exon boundaries of ALMS1 were directly sequenced. SETTING: The study was performed during the annual Alström Syndrome UK multidisciplinary screening clinic. RESULTS: AS patients have early-onset obesity, but body mass index, waist circumference, and body fat from dual-energy x-ray absorptiometry were negatively correlated with age (r = -0.37, P = 0.2; r = -0.84, P = 0.002; and r = -0.6, P = 0.05). Despite this, insulin resistance increased, demonstrated by raised fasting insulin and fall in homeostasis model assessment insulin sensitivity with age (r = -0.64, P = 0.02). ALMS1 mutations were identified in 10 of 12 patients, with a potential founder mutation in exon 16 present in five [np 10775del (C); Del3592fs/ter3597]. No genotype-phenotype correlation was observed. CONCLUSIONS: We identified mutations in ALMS1 in more than 80% of patients with no genotype-phenotype correlation. In AS, severe childhood obesity, waist circumference, and body fat decrease with age, whereas insulin resistance increases. The abdominal obesity, insulin resistance, diabetes, hypertriglyceridemia, and hypertension suggest that AS could represent a monogenic model for the metabolic syndrome.

Short-term effects of severe dietary carbohydrate-restriction advice in Type 2 diabetes--a randomized controlled trial.

OBJECTIVE: This study sought to examine the effects of a 3-month programme of dietary advice to restrict carbohydrate intake compared with reduced-portion, low-fat advice in obese subjects with poorly controlled Type 2 diabetes. RESEARCH DESIGN AND METHODS: One hundred and two patients with Type 2 diabetes were recruited across three centres and randomly allocated to receive group education and individual dietary advice. Weight, glycaemic control, lipids and blood pressure were assessed at baseline and 3 months. Dietary quality was assessed at the end of study. RESULTS: Weight loss was greater in the low-carbohydrate (LC) group (-3.55 +/- 0.63, mean +/- sem) vs. -0.92 +/- 0.40 kg, P = 0.001) and cholesterol : high-density lipoprotein (HDL) ratio improved (-0.48 +/- 0.11 vs. -0.10 +/- 0.10, P = 0.01). However, relative saturated fat intake was greater (13.9 +/- 0.71 vs. 11.0 +/- 0.47% of dietary intake, P < 0.001), although absolute intakes were moderate. CONCLUSIONS: Carbohydrate restriction was an effective method of achieving short-term weight loss compared with standard advice, but this was at the expense of an increase in relative saturated fat intake.

Hypertriglyceridaemia in Alström's syndrome: causes and associations in 37 cases.

OBJECTIVE: To document frequency of severe hypertriglyceridaemia in Alström's syndrome (AS) and its relationship to hepatic and renal function, glycaemia and insulin resistance. PATIENTS AND METHODS: Thirty-seven subjects with AS aged 5-35 years, 51% male, were assessed at multidisciplinary clinics in Canada, UK and Italy. Diagnostic criteria were: severe cone/rod dystrophy leading to severe visual impairment in early childhood, sensorineural deafness, moderate overall obesity and normal intelligence. Three patients were treated with thyroxine for primary hypothyroidism and one female patient for secondary amenorrhoea with 20 micro g ethinyloestradial combined oral contraceptive. Two male patients were receiving monthly intramuscular testosterone enanthate for secondary hypogonadism. Fasting bloods were taken for serum insulin, serum glucose, serum triglycerides, hepatic and renal function and glycosylated Hb. Triglyceride levels > 8 mmol/l and fasting serum insulin levels > 16 microunits/ml were considered to represent severe hypertriglyceridaemia and severe insulin resistance, respectively. All subjects with (23) hypertriglyceridaemia also had high insulin resistance, as measured by HOMA modelling. However, there was no significant correlation between log tyriglyceride and log serum insulin or HOMA in the whole group (P = 0.2 and 0.14, respectively). There was no clear relationship between serum triglyceride levels and age, body mass index (BMI), hepatic or renal impairment or glycaemia. CONCLUSION: The first overview of serum triglyceride levels in a significant number of reported cases of Alström Syndrome shows an overlap between severe hypertriglyceridaemia and severe hyperinsulinism, but not a direct correlation between the two nor with insulin resistance measured by HOMA. Triglyceride levels were not related to glycaemia, hepatic or renal dysfunction.

Five year results of a prospective very low calorie diet or conventional weight loss programme in type 2 diabetes.

AIMS: To complete 5-year follow-up of an intensive weight loss programme in established type 2 diabetic subjects. METHODS: Forty-five obese type 2 diabetic subjects, Body mass index (BMI) > 30, expressed interest in an intensive weight loss programme. Group 1 comprised 15 who selected very low calorie diet (VLCD), Group 2, 15 selected intensive conventional diet and exercise (ICD), 15 failed to follow either programme. Group sessions of eight to 15 subjects continued weekly for 6 months, then monthly for 12 months with prospective recording at 3, 6 and 12 months and then annually of quality of life, BMI, waist/hip ratio, blood pressure, fasting blood glucose, serum fructosamine and serum lipids. RESULTS: Weight loss was slower in the intensive conventional diet group than in the VLCD group, but better maintained at 5 years: group 1, 4.8 +/- 6 kg; group 2, 8.9 +/- 4 kg. In the intensive conventional diet group, 5 year high-density lipoprotein cholesterol was increased 1.78 +/- 0.26 mmol L-1 vs. 1.10 +/- 0.32 mmol L-1 at baseline, and diastolic blood pressure reduced 74.5 +/- 13.3 vs. 85.5 +/- 13.3 at baseline, both P < 0.05. CONCLUSIONS: Out-patient VLCD treatment proved safe and effective in overweight diabetic subjects but those who chose conventional diet and exercise had a slower but more sustained weight loss. Diabetic patients willing to attempt VLCD may safely lose sufficient weight to allow major surgery, but weight regain is inevitable. Patients willing to undertake a long-term group programme of conventional diet can sustain significant weight loss for 5 years, but still require antidiabetic medication.

An intensive weight loss programme in established type 2 diabetes and controls: effects on weight and atherosclerosis risk factors at 1 year.

The efficacy, safety, and effect on cardiovascular risk factors of two intensive weight loss programmes in overweight Type 2 diabetic subjects were studied. The patients were recruited from hospital diabetic clinics and control obese subjects from the community. Obese (BMI >30) patients with Type 2 diabetes mellitus and controls were offered intensive conventional diabetic advice or a very low calorie diet. Weekly 2 h sessions were conducted in two day-room areas of adjacent medical wards of Torbay Hospital. Non-diabetic and diabetic very low calorie diet groups reduced BMI by 6 and 5 kg m(-2), respectively, at 1 year. Waist-hip ratios (-0.06 and -0.05) were also reduced (p = 0.04 and p = 0.01), while HDL/total cholesterol ratios increased (+0.04 and +0.06, p = <0.01). Transient changes in blood pressure and antioxidant vitamin status occurred in the intensive conventional diet group. Fourteen of diabetic very low calorie diet subjects discontinued insulin and oral hypoglycaemic agents for the whole year, and psychological well-being transiently improved. Substantial weight loss and improvement in cardiovascular risk factors could be maintained for 1 year in Type 2 diabetic patients by the use of a very low calorie diet.

Diabetes and alternative medicine: cause for concern.

'Alternative' medicines are becoming increasingly popular, and in this paper we describe our experience with alternative approaches to orthodox diabetes management. Four patients with insulin-dependent diabetes reduced or stopped their insulin in favour of therapeutic approaches including prayer, faith healing, unusual diets, and supplements of vitamins and trace elements. This resulted in ketoacidosis in three, in one case life-threatening; and weight loss and hyperglycaemia in the other. One patient developed serious retinopathy. Additionally, eight other types of alternative diabetic treatment are described, not as far as we know associated with such serious complications. These include homeopathy, reflexology, meditation, herbal treatment, 'cellular nutrition', 'subconscious healing', 'pearl therapy' (drinking milk in which pearls have been boiled) and 'astrotherapy' (typing pieces of coral around the arm). Diabetes is a chronic incurable disease, for which modern treatments remain somewhat unsatisfactory. It is therefore perhaps not surprising that some patients seek alternative treatments with more attractive claims. Diabetes health professionals need to be aware of the potential dangers associated with some of these treatments.

Glycosylated haemoglobin in uraemia.

Glycosylated haemoglobin (GHb) was measured in 71 patients with stable chronic renal failure by the thiobarbituric acid (TBA) reaction and by agar gel electrophoresis. Nineteen patients were diabetic. Of the non-diabetics, 22 were treated conservatively (including 8 children), 15 by maintenance haemodialysis, and 15 by continuous ambulatory peritoneal dialysis. GHb measured by both methods correlated with postprandial blood glucose levels. There was a significant discrepancy between the two methods only in patients with serum urea concentrations greater than 30 mmol/l, mean +/- SD, (6.8 +/- 2.6% vs 8.2 +/- 2.5% for TBA and electrophoresis, respectively). This difference, delta GHb, correlated with serum urea, serum creatinine, and serum bicarbonate, but after logistic regression of results from all 71 patients only serum urea was associated with delta GHb. Lower haemoglobin and GHb and high fetal haemoglobin concentrations in the haemodialysis group suggested increased haemolysis in these patients. Measurement of GHb by the TBA method and by agar gel electrophoresis remain useful indicators of hyperglycaemia in patients with mild, stable chronic renal failure.