Clinical inertia is the enemy of therapeutic success in the management of diabetes and its complications: a narrative literature review.

Diabetes mellitus is a chronic disease characterized by high social, economic and health burden, mostly due to the high incidence and morbidity of diabetes complications. Numerous studies have shown that optimizing metabolic control may reduce the risk of micro and macrovascular complications related to the disease, and the algorithms suggest that an appropriate and timely step of care intensification should be proposed after 3 months from the failure to achieve metabolic goals. Nonetheless, many population studies show that glycemic control in diabetic patients is often inadequate. The phenomenon of clinical inertia in diabetology, defined as the failure to start a therapy or its intensification/de-intensification when appropriate, has been studied for almost 20 years, and it is not limited to diabetes care, but also affects other specialties. In the present manuscript, we have documented the issue of inertia in its complexity, assessing its dimensions, its epidemiological weight, and its burden over the effectiveness of care. Our main goal is the identification of the causes of clinical inertia in diabetology, and the quantification of its social and health-related consequences through the adoption of appropriate indicators, in an effort to advance possible solutions and proposals to fight and possibly overcome clinical inertia, thus improving health outcomes and quality of care.

Impact of a chronic care model based on patient empowerment on the management of Type 2 diabetes: effects of the SINERGIA programme.

AIMS: Several chronic care models for diabetes have been implemented in Italy, although conclusive data on their effectiveness are lacking. In the Cusano-Milanino diabetes clinic, patients with Type 2 diabetes with a stable disease/therapy (i.e. a steady level of HbA(1c) without need for therapy changes) are included in the SINERGIA programme: diabetologists, nurses and dietitians empower patients and telemedicine resources are utilized efficiently. METHODS: Clinical outcomes measured in the year before and after the initiation of SINERGIA were compared. A generalized hierarchical linear regression model for repeated measures was used. RESULTS: Altogether, 1004 patients were included; baseline characteristics were (mean ± sd): age 66.6 ± 6.2 years, 54.1% male, diabetes duration 10.8 ± 7.7 years, BMI 29.5 ± 4.8 kg/m(2) , HbA(1c) 6.9 ± 0.9% (52 ± 14 mmol/mol); 72.9% of patients were treated with anti-hypertensive drugs; 32.7% were treated with lipid-lowering drugs. After a median follow-up of 12 months (range 6-24 months), the proportion of patients with HbA(1c) ≤ 7.0% (≤ 53 mmol/mol) increased from 32.7 to 45.8% (P<0.0001), while those with HbA(1c) ≥9% (≥75 mmol/mol) decreased from 10.5 to 4.3% (P<0.0001). Patients with LDL cholesterol <100 mg/dl (<2.59 mmol/l) increased from 40 to 47% (P <0.0001), while those with LDL cholesterol ≥130 mg/dl (≥3.36 mmol/l) decreased from 26.6 to 19.7%; blood pressure levels were slightly improved. The mean number of face-to-face encounters decreased from (median and range) 2.8 (2.3-3.4) to 2.3 (1.9-2.7) (P<0.0001) visits per patient/year. CONCLUSIONS: The SINERGIA model is effective in improving metabolic control and major cardiovascular risk factors, while allowing diabetologists to dedicate more time to patients with more acute disease.

Effects of propionyl-L-carnitine topical irrigation in distal ulcerative colitis: a preliminary report.

BACKGROUND/AIMS: To study the tolerability of propionyl-L-carnitine administered as rectal irrigation and its efficacy in improving the clinical picture of distal ulcerative colitis. METHODOLOGY: Ten male subjects (aged 18 to 55 years, with a body mass index ranging from 21 to 25 Kg/m2) with distal ulcerative colitis were treated with propionyl-L-carnitine enemas (6 g in 200 mL physiological solution) twice a day over 120 minutes each. All subjects had a disease activity index from 0 to 1. A clinical, laboratory, endoscopy and biopsy evaluation was performed at baseline and 14 days after treatment. Serum tumor necrosis factor-alpha and interleukin-2 concentration was measured. RESULTS: No side effects were reported by the entire patient population and the clinical conditions remained constant throughout the study period. The disease activity index improved significantly between the beginning and the end of the study in 80% of the patients. Histologic features (mucosal erosion, distortion of crypt architecture, inflammation and lamina propria gap) significantly improved in all treated patients. Serum interleukin-2 levels did not change significantly after propionyl-L-carnitine treatment (respectively: 14.7 +/- 15.8 before vs. 9.9 +/- 13.2 pg/mL), while tumor necrosis factor-alpha levels were undetectable both before and after propionyl-L-carnitine administration. CONCLUSIONS: The topical treatment with a new formulation containing propionyl-L-carnitine seems to be safe and effective in improving the histologic features in patients with inactive or mild ulcerative colitis, as an alternative to conventional therapy.

Computing DIT from energy expenditure measures in a respiratory chamber: a direct modeling method.

The possibility of computing Diet Induced Thermogenesis (DIT) is an important feature of metabolic investigations. However, methodological problems have affected the determination of DIT in the indirect calorimetric chamber. DIT has been commonly estimated by regressing energy expenditure on a measure of physical activity. Although used for many years as the only feasible approach to calculate DIT in a respiratory chamber, this traditional method has been criticized because of an apparent underestimation of the DIT, but no alternative method has been suggested so far. The present work proposes to estimate DIT directly by means of a mathematical model. This approach also allows to simultaneously estimate other parameters, namely resting energy expenditure (REE), physical activity (PA) and physical exercise (PE).

Sex hormone-binding globulin levels and cardiovascular risk factors in morbidly obese subjects before and after weight reduction induced by diet or malabsorptive surgery.

One of the main goals of weight reduction in morbidly obese subjects is its benefit on coronary heart disease (CHD) risk. A cross-sectional study was designed to randomly assign 79 morbidly obese subjects (27 men and 52 women; age: 30-45 years) either to a diet protocol (20 kcal per kg fat-free mass (FFM); 55% carbohydrates, 30% fat, and 15% proteins) or to malabsorptive surgery (biliopancreatic diversion). Fatness parameters, measured by dual-energy X-ray absorptiometry, lipid profile, insulin, leptin, sex steroid hormones and sex hormone-binding globulin (SHBG) levels were compared at baseline and 1 year after the beginning of the study. The data showed that plasma SHBG levels, but not testosterone levels, correlated negatively to fasting insulin levels and positively to HDL-cholesterol in both men and women. Total leptin levels were significantly lower (P<0.0001) in post-BPD subjects of both sexes compared to dietary treated obese subjects. The logarithm of plasma leptin correlated significantly and positively with insulin but negatively with SHBG.A step-down regression analysis showed that FFM and SHBG, but not insulin levels, were the most powerful independent variables for predicting HDL-cholesterol levels in morbidly obese patients. The negative relationship between SHBG levels and CHD risk appears to be mediated by a concomitant variation in body fatness. Finally, in obese patients, SHBG levels seem to be an indicator of total adiposity rather than an index of an altered insulin/glucose homeostasis.

A model for glucose control of insulin secretion during 24 h of free living.

The aim of this work was to develop a mathematical model describing the functional dependence of insulin secretion on plasma glucose concentrations during 24 h of free living. We obtained hourly central venous blood samples from a group of healthy volunteers who spent 24 h in a calorimetric chamber, where they consumed standardized meals. Insulin secretory rates were reconstructed from plasma C-peptide concentrations by deconvolution. The relationship between insulin release and plasma glucose concentrations was modeled as the sum of three components: a static component (describing the dependence on plasma glucose concentration itself, with an embedded circadian oscillation), a dynamic component (modeling the dependence on glucose rate of change), and a residual component (including the fraction of insulin secretion not explained by glucose levels). The model fit of the individual 24-h secretion profiles was satisfactory (within the assigned experimental error of glucose and C-peptide concentrations). The static component yielded a dose-response function in which insulin release increased quasi-linearly (from 40 to 400 pmol/min on average) over the range of 4-9 mmol/l glucose. The dynamic component was significantly different from zero in coincidence with meal-related glucose excursions. The circadian oscillation and the residual component accounted for the day/night difference in the ability of glucose to stimulate insulin release. Over 24 h, total insulin release averaged 257+/-58 nmol (or 43+/-10 U). The static and dynamic component together accounted for approximately 80% of total insulin release. The model proposed here provides a detailed robust description of glucose-related insulin release during free-living conditions. In nondiabetic subjects, non-glucose-dependent insulin release is a small fraction of total insulin secretion.

Acetyl-L-carnitine infusion increases glucose disposal in type 2 diabetic patients.

Little information is available in the literature on the effect of L-carnitine to improve glucose disposal in healthy control subjects and type 2 diabetic patients. No data are reported on the pharmacological properties of acetyl-L-carnitine (ALC) in type 2 diabetes mellitus. The present study evaluates glucose uptake and oxidation rates with either ALC or placebo administration in 18 type 2 diabetic patients. On different days, each patient received both a primed-constant infusion of ALC (5 mg/kg body weight [BW] priming bolus and either 0.025, 0.1, or 1.0 mg/kg BW/min constant infusion) and a comparable placebo formulation. During the infusion period, continuous indirect calorimetric monitoring and a euglycemic-hyperinsulinemic clamp (EHC) study were performed. The total end-clamp glucose tissue uptake (M value) was significantly increased by the administration of ALC (from 3.8 to 5.2 mg/kg/min, P = .006), and the dose dependence of this effect reached borderline statistical significance (P = .037). The increase in the M/I ratio was also highly significant after ALC administration (from 3.9 to 5.8 x 10(-2) mg/kg/min/(microUI/mL, P < .001), while no statistically significant effect was attributable to the different dosages. The increase in the M value was related to increased glucose storage (highly significant effect of ALC) rather than increased glucose oxidation (no statistical significance). In conclusion, the effect of ALC on glucose disposal has no relationship to the amount administered. This could be due to an effect of ALC on the enzymes involved in both the glycolytic and gluconeogenetic pathways, and a possible reversibility of glycogen synthase inhibition in diabetic subjects.

Body composition and energy expenditure after weight loss following bariatric surgery.

OBJECTIVES: To assess the effectiveness of biliopancreatic diversion (BPD) in the treatment of morbid obesity and to evaluate how the procedure affects body weight. SUBJECTS: Fourteen morbidly obese subjects studied before and 30 months after BPD and fifteen healthy volunteers matched for age, sex and height (controls). METHODS: Comparison of the following parameters were made in the study groups before surgery and 30 months after BPD and with those of the controls group: fat mass, fat-free mass, non-protein substrate oxidation, basal metabolic rate, plasma glucose, insulin and free fatty acid concentrations. RESULTS: Obese subjects lost 60.38+/-10.71 kg of weight during 18 months following surgery and then remained stable for another 12 months, when this study was performed. Weight loss was substantially due to a loss of fat mass (FM: 60.13+/-13.01 kg before and 19.02+/-8.61 kg after BPD; p<0.001). FM were not statistically different between post-obese subjects and controls; however, post-obese patients retained significantly more fat free mass (FFM) than controls. Subsequently, basal metabolic rates of post-obese subjects were higher than those of the control group (p<0.05). Fasting non-protein respiratory quotient (npRQ) was significantly lower before BPD than 30 months after the surgery (0.798+/-0.04 vs. 0.90+/-0.048, p<0.001), suggesting that, while obese, patients oxidized more lipids than carbohydrates. Moreover, fasting and two-hour plasma glucose and insulin concentrations decreased significantly after BPD to values comparable to those of the control group. CONCLUSION: Weight loss in obese patients after BPD is mainly due to lipid malabsorption, but increased energy expenditure associated with retaining a high FFM in physically active post-obese subjects may also play a role, enabling them to maintain long-term reduced body weights.

L-carnitine improves glucose disposal in type 2 diabetic patients.

OBJECTIVE: Aim of the present study is to evaluate the effects of L-carnitine on insulin-mediated glucose uptake and oxidation in type II diabetic patients and compare the results with those in healthy controls. DESIGN: Fifteen type II diabetic patients and 20 healthy volunteers underwent a short-term (2 hours) euglycemic hyperinsulinemic clamp with simultaneous constant infusion of L-carnitine (0.28 micromole/kg bw/minute) or saline solution. Respiratory gas exchange was measured by an open-circuit ventilated hood system. Plasma glucose, insulin, non-esterified fatty acids (NEFA) and lactate levels were analyzed. Nitrogen urinary excretion was calculated to evaluate protein oxidation. RESULTS: Whole body glucose uptake was significantly (p<0.001) higher with L-carnitine than with saline solution in the two groups investigated (48.66+/-4.73 without carnitine and 52.75+/-5.19 micromoles/kg(ffm)/minute with carnitine in healthy controls, and 35.90+/-5.00 vs. 38.90+/-5.16 micromoles/kg(ffm)/minute in diabetic patients). Glucose oxidation significantly increased only in the diabetic group (17.61+/-3.33 vs. 16.45+/-2.95 micromoles/kg(ffm)/minute, p<0.001). On the contrary, glucose storage increased in both groups (controls: 26.36+/-3.25 vs. 22.79+/-3.46 micromoles/kg(ffm)/minute, p<0.001; diabetics: 21.28+/-3.18 vs. 19.66+/-3.04 micromoles/kg(ffm)/minute, p<0.001). In type II diabetic patients, plasma lactate significantly decreased during L-carnitine infusion compared to saline, going from the basal period to the end-clamp period (0.028+/-0.0191 without carnitine and 0.0759+/-0.0329 with carnitine, p<0.0003). CONCLUSIONS: L-carnitine constant infusion improves insulin sensitivity in insulin resistant diabetic patients; a significant effect on whole body insulin-mediated glucose uptake is also observed in normal subjects. In diabetics, glucose, taken up by the tissues, appears to be promptly utilized as fuel since glucose oxidation is increased during L-carnitine administration. The significantly reduced plasma levels of lactate suggest that this effect might be exerted through the activation of pyruvate dehydrogenase, whose activity is depressed in the insulin resistant status.

Alterations of nutritional status in the main gastrointestinal pathologies.

An impairment of nutritional status up to real malnutrition can frequently be associated to gastrointestinal diseases. The diseases of the gastrointestinal tract can be divided into five groups: those hampering the nutrient physiological transit (especially neoplastic diseases); those affecting the intestinal mucosa (such as chronic inflammatory bowel disease); those determining intraluminal maldigestion; the hepato-biliary diseases and finally, the diseases of the pancreas. In order to correctly evaluate the nutritional status of an individual, besides the determination of the common biochemical parameters, body composition by direct and indirect techniques and energy metabolism by indirect calorimetry should be measured. Patients affected by Crohn's disease showed a lower fat mass content along with higher lipid oxidation compared to patients affected by ulcerative colitis. Patients with coeliac disease at diagnosis had a reduction in both fat and fat-free mass content along with an increased utilisation of carbohydrates as fuel substrate. There are many factors potentially leading to severe malnutrition in pancreatic diseases, especially in the acute form. Due to the primary role played by the liver in the metabolism of energy substrates, an impaired nutritional status might be commonly found in cirrhotic patients. In this connection, our group reported an increased energy expenditure and lipid oxidation, and an insulin-resistant state in compensated liver cirrhotic patients. These alterations seemed to precede and probably to lead to liver-disease-related malnutrition.

Wasting in gastrointestinal tract cancers: clinical and etiologic aspects.

One of the major complications found in patients affected by malignancy of the gastrointestinal tract is represented by an alteration of nutritional status, up to real cachexia. The factors responsible for the severe nutritional deficiencies are: metabolic alterations, which involve carbohydrate, lipid and protein metabolism; the reduced availability of nutritional substrates, due to neoplastic growth that, by expanding locally or destroying the affected organ, determines alterations of deglutition, digestion and food absorption; the effects of surgical therapy, radiotherapy and chemotherapy, which are able to cause temporary or permanent nutritional deficiencies; the effects of immunological mediators, and above all of tumor necrosis factor-alpha (TNF-alpha). In fact, TNF-alpha is considered the main mediator of cancer cachexia as it is responsible for different metabolic alterations, both directly and by the activation of other mediators, such as lipid mobilizing factor (LMF) and protein mobilizing factor (PMF). In addition, a negative energy balance in cancer patients could occur as a consequence of increased energy requirements. In this connection, patients with different neoplasia localisation, show high or within the normal range energy expenditure values. These data indicate that the increase in energy metabolism is not likely to represent the main determining factor in neoplastic cachexia. In conclusion, since patients affected by malignancy of the gastrointestinal tract showed a reduction in body weight, fat and fat-free mass, accurate evaluation of nutritional status should be useful in the management and follow-up of these patients.

Plasma levels of fibronectin in patients with chronic viral and alcoholic liver disease.

BACKGROUND/AIMS: Plasma fibronectin levels are reportedly decreased in patients with cirrhosis, while increases are associated with acute and chronic hepatitis. We studied 101 patients with chronic liver disease to determine the relationship between disease etiology and plasma fibronectin levels. METHODOLOGY: Plasma fibronectin levels and standard liver function parameters were measured in all patients and 11 healthy controls. Antipyrine metabolism was also evaluated in 39 patients. Results were analyzed according to etiology (HBV, HCV, alcohol abuse) and histological findings (chronic active hepatitis (CAH) with/without fibrosis, steatosis, cirrhosis). RESULTS: The fibronectin levels were similar in patients with HBV, HCV and alcohol-related disease. Analysis of the groups based on histological features showed that fibronectin levels in cirrhotics (mean 270.69 microg/ml) were significantly lower than those of the control (mean 372.00 microg/ml) and other patient groups (steatosis: 470.37 microg/ml; CAH: 417.93 microg/ml; CAH and fibrosis: 426.72 microg/ml). Plasma fibronectin displayed a positive correlation with antipyrine metabolism and parameters of hepatic synthesis. CONCLUSIONS: Plasma fibronectin appears to be an index of hepatic parenchymal function but shows no relation to the etiology of the liver disease.