Jannik Hilsted

Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

Effect of sibutramine on weight maintenance after weight loss: a randomised trial*

BACKGROUND Sibutramine is a tertiary amine that has been shown to induce dose-dependent weight loss and to enhance the effects of a low-calorie diet for up to a year. We did a randomised, double-blind trial to assess the usefulness of sibutramine in maintaining substantial weight loss over 2 years. METHODS Eight European centres recruited 605 obese patients (body-mass index 30-45 kg/m2) for a 6-month period of weight loss with sibutramine (10 mg/day) and an individualised 600 kcal/day deficit programme based on measured resting metabolic rates. 467 (77%) patients with more than 5% weight loss were then randomly assigned 10 mg/day sibutramine (n=352) or placebo (n=115) for a further 18 months. Sibutramine was increased up to 20 mg/day if weight regain occurred. The primary outcome measure was the number of patients at year 2 maintaining at least 80% of the weight lost between baseline and month 6. Secondary outcomes included changes in uric acid concentrations and glycaemic and lipid variables. Analysis was by intention to treat. FINDINGS 148 (42%) individuals in the sibutramine group and 58 (50%) in the placebo group dropped out. Of the 204 sibutramine-treated individuals who completed the trial, 89 (43%) maintained 80% or more of their original weight loss, compared with nine (16%) of the 57 individuals in the placebo group (odds ratio 4.64, p<0.001). Patients had substantial decreases over the first 6 months with respect to triglycerides, VLDL cholesterol, insulin, C peptide, and uric acid; these changes were sustained in the sibutramine group but not the placebo group. HDL cholesterol concentrations rose substantially in the second year: overall increases were 20.7% (sibutramine) and 11.7% (placebo, p<0.001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood pressure by 2.3 mm Hg (9.4), and pulse rate by 4.1 beats/min (11.9). INTERPRETATION This individualised management programme achieved weight loss in 77% of obese patients and sustained weight loss in most patients continuing therapy for 2 years. Changes in concentrations of HDL cholesterol, VLDL cholesterol, and triglyceride, but not LDL cholesterol, exceed those expected either from weight loss alone or when induced by other selective therapies for low concentrations of HDL cholesterol relating to coronary heart disease.

Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management

The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non‐dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost‐effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN. Copyright

Effect of glucagon-like peptide-1 (proglucagon 78-107amide) on hepatic glucose production in healthy man.

The newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1) (proglucagon 78-107amide), stimulates insulin secretion and inhibits glucagon secretion in man and may therefore be anticipated to influence hepatic glucose production. To study this, we infused synthetic GLP-1 sequentially at rates of 25 and 75 pmol.kg-1.h-1 into eight healthy volunteers after an overnight fast and measured plasma concentrations of glucose, insulin, and glucagon and glucose turnover by a technique involving infusion of 3-3H-glucose. Plasma levels of GLP-1 increased by 21.3 +/- 3.1 and 75.4 +/- 3.2 pmol/L during the infusion, changes that were within physiologic limits. In a control experiment only saline was infused. During GLP-1 infusion, plasma glucose level decreased significantly (from 5.3 +/- 0.1 to 4.7 +/- 0.1 and 4.3 +/- 0.1 pmol/L at the end of the two infusion periods). Despite this, plasma insulin level increased significantly (from 20.5 +/- 2.9 to a peak value of 33.5 +/- 5.2 pmol/L during the second period), and plasma glucagon level decreased (from 9.3 +/- 1.7 to 7.1 +/- 1.0 pmol/L). Glucose rate of appearance (Ra) decreased significantly to 75% +/- 6% of the preinfusion values during GLP-1 infusion. Glucose disappearance rate (Rd) did not change significantly, but glucose clearance increased significantly compared with saline. All parameters of glucose turnover remained constant during saline infusion. We conclude that GLP-1 may potently control hepatic glucose production and glucose clearance through its effects on the pancreatic glucoregulatory hormones. The effect of GLP-1 on glucose production is consistent with its proposed use in the treatment of type II diabetes.

The impact of obesity, fat distribution, and energy restriction on insulin-like growth factor-1 (IGF-1), IGF-binding protein-3, insulin, and growth hormone

The aim of this study was to characterize the association between serum insulin-like growth factor-1 (IGF-1) and obesity, as well as fat distribution, before and during moderate energy restriction (1,200 kcal/d). In 51 females and nine males having a body mass index (BMI) between 27 and 39 kg/m2, relationships between serum IGF-1, IGF-binding protein-3 (IGFBP-3), insulin, growth hormone (GH), blood glucose, and anthropometric measurements of body fat were examined. The patients were studied before treatment and again after 8 and 16 weeks of dieting. Visceral adipose tissue (AT) was estimated by anthropometric computed tomography (CT)-calibrated equations. In females, IGF-1 was inversely associated with the abdominal sagittal diameter (SagD) and with the visceral AT (r = -.41, P = .006). No significant correlations were found between IGF-1 and BMI or other indices of adiposity. Weight loss caused a temporary increase in IGF-1 concentrations (P = .03) and continued decrements in blood glucose levels (P = .0004 at 16 weeks). A statistically significant inverse correlation between IGF-1 and blood glucose levels was present before (r = -.30, P = .02) and after 8 (r = -.37, P = .007) and 16 (r = .02, P = .02) weeks of dietary treatment. Both serum IGF-1 and insulin levels were positively correlated with serum IGFBP-3 levels (r = .34, P = .009 and r = .34, P = .008, respectively). We conclude that IGF-1 levels in obese females reflect the intraabdominal fat mass rather than obesity per se. IGF-1 and blood glucose levels are inversely correlated in obesity before and during energy restriction.

Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity. Results from the European multi-centre STORM trial. Sibutramine Trial of Obesity Reduction and Maintenance.

BACKGROUND: In this report we assess pre-treatment determinants of weight loss and maintenance outcome in The Sibutramine Trial of Obesity Reduction and Maintenance (STORM), a 2 y randomized, double-blind, placebo-controlled, European multicenter study examining the effect of sibutramine (Sib) on inducing and maintaining weight loss in obese subjects.MATERIAL: A total of 605 obese patients (BMI: 30–45 kg/m2) of both gender were included from eight European centers and treated for 24 months. The patients were treated for the initial 6 months by Sib (10 mg/day) and a low-fat low-energy, individualized diet (600 kcal/day deficit). The 467 patients who achieved >5% weight loss after 6 months were randomized 3:1 to Sib (10 mg/day) (Sib/Sib) and placebo (Sib/Pla) for weight maintenance over a further 18 months.MAIN OUTCOME AND ANALYSES: Pre-treatment individual characteristics were assessed as predictors of 6 months weight loss (kg) and 24 months weight maintenance using simple and multivariate correlation and regression analyses.RESULTS: In univariate analyses, the 6 month weight loss (n=505) was positively associated with pre-treatment body weight (r=0.27), height (r=0.18), fat-free mass (r=0.21) (all P<0.001), fat mass (r=0.13, P0.03), and resting metabolic rate (r=0.13, P<0.003). However, no relation was found with age, gender, smoking status, age at onset of obesity, or number of previous slimming attempts. The same predictors were found for weight change to endpoint in the Sib/Sib group (n=350), while no predictors were identified in the Sib/Pla (n=114). In the multivariate regression analysis only pre-treatment body weight predicted weight loss at 6 months (P<0.001). Weight change (kg) to 24 month was predicted by: 4.34+0.07*body weight (kg)−4*treatment (Sib=1, Pla=0)−0.06*age (y), (r 2=8%, P<0.001).CONCLUSION: Only pre-treatment body weight seems to be an important independent predictor of 6 months weight loss and 24 month weight maintenance in this study on diet and Sib. As only 8% of the variation in 24 months weight change could be explained by the predictors, the clinical value of this information is limited.International Journal of Obesity (2001) 25, 496–501

Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency

SummaryBackground. Calcium and vitamin D homeostasis seem to be abnormal in patients with exocrine pancreatic dysfunction resulting from cystic fibrosis. Only a few studies have evaluated and described bone mineral metabolism in patients with chronic pancreatitis and pancreatic insufficiency. Methods. Thirty-two patients with chronic pancreatitis and residual exocrine pancreatic function (group 1) and 26 patients with pancreatic exocrine insufficiency (i.e., meal-stimulated intraduodenal lipase <10% of lowest normal range and steatorrhea) (group 2) were studied. Serum levels of total calcium, phosphate, 25 (OH)D, 1.25(OH)2D, alkaline phosphatase, and parathyroid hormone were measured. Bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM), and fat mass (FM) were measured using a dual-energy X-ray absorptiometry (DXA) scanner. Results. Alcohol was a causative factor in 79% of the patients. Fifty-six percent in group 1 and 69% in group 2 had Z-scores of the BMD<−1. The mean Z-score was −1.16±1.29 in group 1 and −1.32±0.90 in group 2. The mean Z-score of the BMC was −1.02±1.17 vs −1.39±0.987. In both groups mean 25 (OH)D and mean 1.25(OH)2D were below reference range. Plasma concentrations of albumin-corrected calcium, alkaline phosphatase, and parathyroid hormone were in the upper range of the reference range. Mean Z-scores of LBM were −0.69±1.34 in group 1 vs −1.01±1.12 in group 2 and Z-scores of FM were −0.27±1.70 in group 1 vs −0.95±1.01 in group 2 (p<0.05). Conclusion. Patients with chronic pancreatitis, in particular patients with advanced disease and steatorrhea, are at risk of developing singificant bone loss. Despite normal body mass index the patients are characterized by loss of lean body mass and fat mass. The present study shows that these patients have decreased serum levels of vitamin D metabolites and low bone mass.

Hormonal, Metabolic, and Cardiovascular Responses to Hypoglycemia in Diabetic Autonomic Neuropathy

Hormonal, metabolic, and cardiovascular responses to insulin-induced hypoglycemia were investigated in 10 juvenile-onset diabetics who showed signs of autonomic neuropathy, in 8 control patients of similar age and duration of diabetes without neuropathy, and in 6 healthy subjects. In an attempt to normalize intermediary metabolism, the diabetics were treated with soluble insulin only (given subcutaneously and intravenously) for 48 h preceding the study. Plasma epinephrine concentrations were significantly lower in patients with autonomic neuropathy before the experiment as well as 15 min after serum glucose nadir compared with diabetics without neuropathy (P < 0.05), indicating impaired sympathoadrenal activity. Plasma norepinephrine responses did not differ significantly. No significant increase was found in glucagon concentrations in patients with autonomic neuropathy, whereas a small increment was found in diabetics without neuropathy. Growth hormone and cortisol responses were similar in the two patient groups, and serum free insulin concentrations were also similar. In spite of blunted responses of glucagon and of epinephrine in the patients with autonomic neuropathy, serum glucose responses were similar to those of the diabetics without autonomic neuropathy. Furthermore, rate of lipolysis, as judged from FFA and glycerol concentrations, as well as systolic blood pressure increments were significantly greater (P < 0.05) in patients with autonomic neuropathy than in diabetics without neuropathy. In conclusion, during insulin-induced hypoglycemia, patients with autonomic neuropathy had impaired activation of the adrenal medulla, probably due to sympathetic neuropathy. Furthermore, they had no increase in glucagon concentrations. Compared with noneuro-pathic diabetics, serum glucose recovery was unaffected and lipolytic responses and blood pressure increments were exaggerated, suggesting increased sensitivity of hepatic glycogenolysis, adipose tissue lipolysis, and the cardiovascular system toward the action of catecholamines in diabetics with autonomic neuropathy.

Impaired Cardiovascular Responses to Graded Exercise in Diabetic Autonomic Neuropathy

Six juvenile diabetics [age, 31 ± 2 yr (mean and SEM); duration of diabetes, 15 ± 4 yr] with signs of autonomic neuropathy (decreased beat-to-beat variation in heart rate during deep breathing) and seven control patients of similar age (27 ± 1 yr) and duration of diabetes (14 ± 2 yr) performed graded exercise oh an ergometer cycle. Resting heart rate was higher and the increase in heart rate at the lowest work load (50 W) was diminished in patients with autonomic neuropathy compared with control patients (P < 0.001), indicating a vagal defect. The relationships in autonomic neuropathy between heart rate and systolic blood pressure, respectively, and relative work load (expressed as oxygen uptake — in percent—of individual maximal oxygen uptake) were identical with previous findings in normal subjects during beta-adrenergic receptor blockade, indicating impaired sympathetic activity. Maximal heart rate was 157 ± 9 min−1 in autonomic neuropathy and 181 ± 4 in controls, P < 0.05; maximal systolic blood pressure was 179 ± 11 mm Hg and 197 ± 5, respectively. The greatest tolerable work load was significantly less in patients with autonomic neuropathy (125 ± 13 vs. 161 ± 9 w, P < 0.05). Similarly, maximal oxygen uptake was reduced (1.68 ± 0.21 vs. 2.78 ± 0.18 L/min, 25 ± 3 vs. 38 ± 2 ml/min/kg, P < 0.005). In conclusion, diabetics with decreased beat-to-beat variation in heart rate displayed signs of cardiovascular dysfunction of parasympathetic as well as sympathetic origin during graded exercise.

Hemodynamics in diabetic orthostatic hypotension.

Hemodynamic variables (blood pressure, cardiac output, heart rate, plasma volume, splanchnic blood flow, and peripheral subcutaneous blood flow) and plasma concentrations of norepinephrine, epinephrine, and renin were measured in the supine position and after 30 min of quiet standing. This was done in normal subjects (n = 7) and in juvenile-onset diabetic patients without neuropathy (n = 8), with slight neuropathy (decreased beat-to-beat variation in heart rate during hyperventilation) (n = 8), and with severe neuropathy including orthostatic hypotension (n = 7). Blood pressure decreased precipitously in the standing position in the diabetics with orthostatic hypotension, whereas moderate decreases were found in the other three groups. Upon standing, heart rate rose and cardiac output and plasma volume decreased similarly in the four groups. The increases in total peripheral resistance, splanchnic vascular resistance and subcutaneous vascular resistance were all significantly lower (P less than 0.025) in the patients with orthostatic hypotension compared with the other three groups. The increase in plasma norepinephrine concentrations in the patients with orthostatic hypotension was significantly lower (P less than 0.025) than in the patients without neuropathy, whereas plasma renin responses to standing were similar in the four groups. We conclude that in diabetic hypoadrenergic orthostatic hypotension the basic pathophysiological defect is lack of ability to increase vascular resistance, probably due to impaired sympathetic activity in the autonomic nerves innervating resistance vessels; cardiac output and plasma volume responses to standing are similar to those found in normal subjects and in diabetics without neuropathy.