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Our research group has dealt with injection-induced lip hypertrophy (IILH) in insulin-treated subjects for over a decade, focusing on causes and consequences, education, prevention and treatment, comorbidities, and related complications. Stimulated by an excellent Review that recently appeared on the pages of this Journal, we want to contribute insight into IILH. This brief Commentary underlines some key concepts on how to identify, prevent and cure them, pointing out salient aspects derived from our research to provide the scientific community with an as complete as possible overview of evidence-based knowledge and highlight the need for further experimental insights.

The screening and best treatment for coronary heart disease in diabetic patients is still a matter of debate. For this reason the main Italian scientific societies dealing with diabetes and cardiovascular diseases have tried to finalize a document providing shared recommendations based on the available evidence on : 1) how and who to screen for coronary heart disease, 2) methodologies for the characterization of existing coronary heart disease 3) evaluation of the optimal treatment of cardiovascular risk factors and 4) appropriate revascularization procedures. For each of these points, the levels of evidence and strength of recommendations used in the Italian Standard of Care were adopted.

Latent autoimmune diabetes in adults (LADA) includes a heterogeneous population wherein, based on glutamic acid decarboxylase antibody (GADA) titer, different subgroups of subjects can be identified. OBJECTIVE: The aim of the present study was to evaluate GADA titer-related risk for β-cell and other organ-specific autoimmunity in LADA subjects. METHODS: Adult-onset autoimmune diabetes subjects (n=236) and type 2 diabetes (T2DM) subjects (n=450) were characterized for protein tyrosine phosphatase (IA-2IC and IA-2(256-760)), zinc transporter 8 (ZnT8), thyroid peroxidase, (TPO), steroid 21-hydroxylase (21-OH), tissue transglutaminase (tTG), and antiparietal cell (APC) antibodies. RESULTS: High GADA titer compared to low GADA titer showed a significantly higher prevalence of IA-2IC, IA-2(256-760), ZnT8, TPO, and APC antibodies (P≤0.04 for all comparison). 21-OH antibodies were detected in 3.4% of high GADA titer. A significant decreasing trend was observed from high GADA to low GADA and to T2DM subjects for IA-2(256-760), ZnT8, TPO, tTG, and APC antibodies (P for trend≤0.001). TPO was the only antibody showing a different prevalence between gender; low GADA titer and T2DM female patients had a higher frequency of TPO antibody compared to males (P=0.0004 and P=0.0006, respectively), where the presence of high GADA titer conferred an odds ratio of 8.6 for TPO compared to low GADA titer. After subdividing high and low GADA titer subjects according to the number of antibodies, we observed that 73.3% of high GADA titer subjects were positive for at least one or more antibodies, compared to 38.3% of low GADA titer (P

A case of severe autonomic diabetic neuropathy with abolished visceral pain sensitivity is reported. A patient was admitted who presented jaundice without abdominal pain. Diabetes was diagnosed. The pathogenesis of jaundice was traced to the inflammation of a postoperative stenosis of the choledochus. An episode of gallstone disease had occurred 7 years before. Interestingly, although there were stones located both in the gallbladder and in the distal extremity of the choledochus, no pain was present. Possible relationships between gallstone disease and diabetic autonomic neuropathy are discussed.

When considering urogenital complaints occurring during diabetic autonomous neurotherapy , three clinical situations are important due to their frequency and the clinical situation, the considerable effect they have on quality of life. In addition they may also be responsible for severe complications as in the case of diabetic cystopathy . This syndrome is the cause of considerable subjective disturbances even though it may be diagnosed instrumentally in its early, completely asymptomatic stage. The complaint evolves inevitably towards bladder denervation, chronic urinary retention and more or less severe septic complications. Retrograde ejaculation may lead to the loss of procreative ability as in the case of neurogenic impotence in diabetics. These three autonomous neuropathic situations occur quite frequently, especially in older subjects who have suffered from diabetes for more than ten years. Often the three syndromes are interconnected or linked to autonomous or peripheric neuropathic complaints affecting other areas. The few therapeutic measures practised have not proved very conclusive. Only a diligent examination of signs and symptoms with the aim of early diagnosis and the maintenance of good glycometabolic balance are considered to be at all effective as preventive measures.

The purpose of this study was to assess the relative diagnostic value of two-dimensional echocardiography (2D-Echo) and biplane left ventricular cineangiography (CV) for detecting the presence of left ventricular mural thrombi (LVT) in selected patients (pts) with left ventricular aneurysm (LVA). The Echocardiographic and Angiographic data of 19 pts selected from a group of 58 pts with coronary artery disease who underwent surgery for aorto-coronary bypass and/or aneurismectomy, were retrospectively examined. The presence of LVA was shown at surgery in all patients, located near the cardiac apex in 10 pts, at the level of the antero-septal wall of left ventricle in 7 pts and of the antero-lateral wall in 2 pts. In 11 of the 19 pts (57.9%) a LVT was identified at surgery. The thrombus was large (greater than 2 cmq) in 6 pts and small (greater than 2 cmq) in 5 pts. In 10 of the 11 pts with LVT 2D-Echo showed the thrombus prior surgery (sensitivity = 91.6%) whereas CV identified the thrombus only in 7 pts (sensitivity = 73.3%). No false positive diagnosis of LVT was made by the two techniques (specificity = 100%). Six large and 4 small thrombi (1 false negative) were identified by 2D-Echo; 6 large and 1 small thrombi (4 false negative) were identified by CV. In conclusion, 2D-Echo showed a significantly higher sensitivity for LVT than CV in patients with prior Acute Myocardial infarction, especially for small thrombi.

We have studied plasmatic half-life of R-SV administered alone and in association with nicotinic acid, before and after treatment with phenobarbital, in 10 normobilirubinaemic subjects and in 10 patients Gilbert's syndrome, used like controls. Ouer results confirm the existence of some alterations of drug-metabolism produced by associated administration of other drugs, in both healthy and hyperbilirubinaemic subjects, and in these one even more.

We have studied PRA levels in 10 healthy subjects compared with 10 patients affected with essential hypertension (with low PRA) on venous blood samples collected after 8 hours of rest and after 15-20 minutes of slow plain walk. Contemporarely we have taken up arterious pression levels in each class of subjects of these studies. No significant differences of PRA are demonstrable in healthy subjects and in patients affected with essential hypertension. Postural changes in hypertension produces significant rise of PRA, not related to arterial pressure.

Background. Chronic kidney disease (CKD) entails a worse cardiovascular outcome. The aim of our work was to study the relationship between CKD and the achievement of recommended targets for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) in a real-life sample of patients with type 2 diabetes mellitus (T2DM). Methods. We analysed a sample of 116 777 outpatients from the Network of the Italian Association of Clinical Diabetologists; all patients had T2DM and at least one measurement of HbA1c, LDL-c, BP, serum creatinine and albuminuria in the year 2010. The outcome was the achievement of HbA1c, LDL-c and BP values as recommended by International Guidelines. Results. In the entire sample, themean value ofHbA1c was 7.2± 1.2%, of LDL-c was 102 ± 33 mg/dL and of BP was 138/78 ± 19/ 9 mmHg. CKD and its components were associated with poor glycaemic and BP control, notwithstanding greater use of glucose and BP-lowering drugs, while no association was found with LDL-c values. Factors independently related to unsatisfactory glycaemic control included female gender, body mass index, duration of disease and high albuminuria. Men, older people and those taking statins were more likely to reach LDL-c target levels. Male gender, age and high albuminuria strongly affected the achievement of BP targets. Conclusions. CKD or its components, mainly high albuminuria, are associated with failure to reach therapeutic targets, especially for HbA1c and BP, despite a greater use of drugs in patients with T2DM.

Full-text(opens in a new window)|Order document(opens in a new window)|View at Publisher| Export | Download | Add to List | More... Acta Diabetologica Volume 51, Issue 3, June 2014, Pages 447-453 Different prevalence of metabolic control and chronic complication rate according to the time of referral to a diabetes care unit in the elderly (Article) Strollo, F.a , Guarino, G.b, Marino, G.b, Paolisso, G.c, Gentile, S.b a Endocrine-Metabolic Unit, INRCA, Rome, Italy b Department of Clinical and Experimental Medicine, 2nd University of Naples, Naples, Italy c Department of Geriatrics and Metabolic Diseases, 2nd University of Naples, Naples, Italy View additional affiliations View references (35) Abstract The time of diagnosis is crucial for type 2 diabetes mellitus (T2DM) in terms of disease severity and chronic complications, as initial glycated haemoglobin (HbA1c) predicts 5-year cardiovascularmortality. The Italian health-care system relies on about 650 diabetes care units (DCU) interfacing with a large number of general practitioners (GPs). It may thus reach the goal of preventing complications easier than others by adopting a more comprehensive multifactorial approach. To assess whether the interval between diagnosis and referral to the DCU might influence the course of the disease in terms of HbA1c, associated cardiovascular risk factors, drug utilisation, and chronic complications in the elderly, the electronic records of 313 elderly T2DM patients (74.6 ± 4.9 years) followed by their GPs until referral to our DCU were retrospectively analysed for the above-mentioned parameters and divided into an early referral (ER) group (diagnosed within 12 months, n = 111) and a late referral (LR) group (diagnosed>12 months before, n = 202). A further set of 200 patients routinely taken care by our DCU, matched with the LR group for age, gender, and disease duration, was classified as "long-standing follow-up" (LSF) and compared to the others to rule out any confounding effects of long-standing disease per se on the clinical outcomes investigated in our study. About 35% of T2DM patients referred to our DCU within 12 months of diagnosis; the rest did so some 5 years after diagnosis. LR patients displayed worse HbA1c levels (10.8 vs. 7.7%, p < 0.01), used more drugs, and had more than twice as high complication rates as their ER counterparts. Almost all risk factors and complications were lower in the LSF (0.001 < p < 0.05) and ER groups than in the LR group. In both the ER and the LSF groups, we observed a lower burden of diabetes than in the LR group. This rules out the possibility that disease duration might play a major role per se in the burden of the disease in the elderly as opposed to the thoughtful patient care attitude exhibited by the DCU. A better and more efficient organisation has to be developed, including a strong interaction among GPs, diabetes specialists, and elderly people with T2DM allowing the latter to take charge of their own disease management through a sustained empowerment policy.

OBJECTIVE To investigate the quality of type 2 diabetes care according to sex. RESEARCH DESIGN AND METHODS Clinical data collected during the year 2009 were extracted from electronic medical records; quality-of-care indicators were evaluated. Multilevel logistic regression analysis was applied to estimate the likelihood of women versus men to be monitored for selected parameters, to reach clinical outcomes, and to be treated with specific classes of drugs. The intercenter variability in the proportion of men and women achieving the targets was also investigated. RESULTS Overall, 415,294 patients from 236 diabetes outpatient centers were evaluated, of whom 188,125 (45.3%) were women and 227,169 (54.7%) were men. Women were 14% more likely than men to have HbA1c >9.0% in spite of insulin treatment (odds ratio 1.14 [95% CI 1.10–1.17]), 42% more likely to have LDL cholesterol (LDL-C) ≥130 mg/dL (1.42 [1.38–1.46]) in spite of lipid-lowering treatment, and 50% more likely to have BMI ≥30 kg/m2 (1.50 [1.50–1.54]). Women were less likely to be monitored for foot and eye complications. In 99% of centers, the percentage of men reaching the LDL-C target was higher than in women, the proportion of patients reaching the HbA1c target was in favor of men in 80% of the centers, and no differences emerged for blood pressure. CONCLUSIONS Women show a poorer quality of diabetes care than men. The attainment of the LDL-C target seems to be mainly related to pathophysiological factors, whereas patient and physician attitudes can play an important role in other process measures and outcomes.

Early intensive therapy in type 2 diabetes can prevent complications. Nevertheless, metabolic control is often sub-optimal in newly diagnosed patients. This webbased survey aimed to evaluate opinions of physicians about treatment, priorities, and barriers in the care of patients first referred to diabetes clinics. Data on physician attitudes toward therapeutic preferences for two clinical case models (same clinical profile, except HbA1c levels of 8.6 and 7.3% at the first access, respectively) were collected. Participants were asked to rank from 1 (most important) to 6 (least important) a list of priorities and barriers associated with the care of new patients. Overall, 593 physicians participated. In both case models, metformin and education were primary options, although their combination with other classes of drugs varied substantially. Main priorities were ‘‘to teach the patient how to cope with the disease’’ and ‘‘to achieve HbA1c target’’; main barriers were ‘‘lack of time’’ and ‘‘long waiting list’’. At multivariate analyses, physicians from the South of Italy had a twofold higher likelihood to attribute a rank 1–2 to organizational barriers than those operating in the North (South vs. North: OR: 2.4; 95% CI 1.4–4.1; Center vs. North: OR: 2.4; 95% CI 0.9–3.2). In the absence of a widely accepted evidence-based therapeutic algorithm driving the therapeutic choices according to the patient characteristics, prescriptions vary according to physician preferences. Education is perceived as a key-strategy, but organizational barriers and geographic disparities are an obstacle. These findings can drive new strategies to reduce clinical inertia, attitudes variability, and geographic disparities.

OBJECTIVE: Hypoglycemia is common in type 1 diabetes mellitus (T1DM). We aimed to update the incidence of severe and symptomatic hypoglycemia and investigate several correlated factors. METHODS: In this multicenter, observational retrospective study, the data of 206 T1DM patients from a sample of 2,229 consecutive patients seen at 18 diabetes clinics were analyzed. Sociodemographic and clinical characteristics, severe hypoglycemia in the past 12 months, and symptomatic hypoglycemia in the past 4 weeks were recorded with a self-report questionnaire and a clinical form during a routine visit. Poisson multivariate models were applied. RESULTS: A minority of patients accounted for the majority of both severe and symptomatic episodes. The incidence rate (IR) of severe hypoglycemia was 0.49 (0.40-0.60) events/person-years. The incidence rate ratio (IRR) was higher in patients with previous severe hypoglycemia (3.71; 2.28-6.04), neuropathy (4.16; 2.14-8.05), long duration (>20 years, 2.96; 1.60-5.45), and on polypharmacy (1.24; 1.13-1.36), but it was lower when a complication was present. The IR of symptomatic hypoglycemia was 53.3 events/person-years, with an IRR significantly higher among women or patients with better education, or shorter duration or on pumps. The IRR was lower in patients with higher BMI or neuropathy or aged more than 50 years. CONCLUSIONS: Fewer than 20 % of T1DM patients are free from hypoglycemia, with one in six having experienced at least one severe episode in the last year. The distribution is uneven, with a tendency of episodes to cluster in some patients. Severe and symptomatic episodes have different correlates and reflect different conditions.

Introduction: Several data have emphasized the importance of early diagnosis of erectile dysfunction (ED) and meticulous cardiovascular investigation in the type 2 diabetic mellitus (T2DM) patients. Aim: To estimate the prevalence of ED and its associated determinants in a sample of male patients with new or recently diagnosed T2DM. Methods: The SUBITO-DE study is an observational, multicenter, prospective study involving 27 Italian diabetes centers. Male patients recently diagnosed with T2DM were consecutively interviewed by their attending physician at the diabetes care centers and asked whether they had experienced a change in their sexual function or found it unsatisfactory. Those responding positively were then invited to participate in the study. Main Outcome Measure: Several hormonal and biochemical parameters were studied. Results: A nonselected series of 1,503 patients was interviewed, 499 of which (mean age, 58.8±8.8 years) entered the study, yielding a final enrolment rate of 33.3%. ED was classified as mild in 19.4%, mild-to-moderate in 15.4%, moderate in 10.4%, and severe in 21.6% of patients, respectively. In addition, premature ejaculation, delayed ejaculation, and hypoactive sexual desire (HSD) were comorbid in 28.3%, 32.9%, and 58.4%, respectively. Finally, hypogonadism, showed an estimated prevalence of almost 20%. Both organic (at least one chronic DM-associated complication) and psychological factors (severe depressive symptoms) increased the risk of ED. Severe depressive symptoms were also associated with ejaculatory problems, HSD, and hypogonadism. Conclusions: A high prevalence of sexual dysfunction in men with recently diagnosed T2DM was detected. Early diagnosis of ED could help prevent emotional and physical discomfort in men and aid in identifying reversible cardiovascular risk factors. Screening of sexual dysfunction should become a part of routine care in the management of T2DM patients. Corona G, Giorda CB, Cucinotta D, Guida P, Nada E, and Gruppo di studio SUBITO-DE. Sexual dysfunction at the onset of type 2 diabetes: The interplay of depression, hormonal and cardiovascular factors. J Sex Med 2014;11:2065-2073. © 2014 International Society for Sexual Medicine.

Type 2 diabetes is a progressive disease with a complex and multifactorial pathophysiology. Patients with type 2 diabetes show a variety of clinical features, including different “phenotypes” of hyperglycemia (eg, fasting/preprandial or postprandial). Thus, the best treatment choice is sometimes difficult to make, and treatment initiation or optimization is postponed. This situation may explain why, despite the existing complex therapeutic armamentarium and guidelines for the treatment of type 2 diabetes, a significant proportion of patients do not have good metabolic control and at risk of developing the late complications of diabetes. The Italian Association of Medical Diabetologists has developed an innovative personalized algorithm for the treatment of type 2 diabetes, which is available online. According to the main features shown by the patient, six algorithms are proposed, according to glycated hemoglobin (HbA1c, ≥9% or ≤9%), body mass index (≤30 kg/m2 or ≥30 kg/m2), occupational risk potentially related to hypoglycemia, chronic renal failure, and frail elderly status. Through self-monitoring of blood glucose, patients are phenotyped according to the occurrence of fasting/preprandial or postprandial hyperglycemia. In each of these six algorithms, the gradual choice of treatment is related to the identified phenotype. With one exception, these algorithms contain a stepwise approach for patients with type 2 diabetes who are metformin-intolerant. The glycemic targets (HbA1c, fasting/preprandial and postprandial glycemia) are also personalized. This accessible and easy to use algorithm may help physicians to choose a personalized treatment plan for each patient and to optimize it in a timely manner, thereby lessening clinical inertia., Video abstract

Summary Aim Non-insulin-dependent diabetes mellitus (type 2 diabetes) not responding to dietary treatment alone in patients with non-alcoholic liver cirrhosis is characterized by high postprandial hyperglycaemia. The control of postprandial hyperglycaemia in such patients, is generally achieved by the means of progressively higher doses of insulin, with an increasing risk of hypoglycaemia in the late postprandial period. The aim of this study was to evaluate the use of acarbose for the control of postprandial hyperglycaemia in 100 patients with well-compensated liver cirrhosis and type 2 diabetes treated with insulin. Methods The study was double blind with randomization of treatments into acarbose (52 patients) vs. placebo (48 patients) with parallel branches over a period of 28 weeks. Results All patients tolerated the treatments well and no significant variations in liver function tests were observed (

Although there is little information from primary or secondary prevention trials on cholesterol- lowering medication in diabetic patients, the reduction of elevated cholesterol is widely recommended for this group. The American Diabetes Association (ADA) recommends drug therapy in diabetic patients if low density lipoprotein (LDL)-cholesterol remains at > 130 mg/dl, or > 100 mg/dl in patients with macroangiopathy, after dietary intervention. When cholesterol- lowering medication is indicated, the choice of the drug must take into account the other lipid abnormalities that are often present and the need to maintain optimal glycaemic control. In the present study we compared the ef®cacy and safety of the novel HMG-CoA reductase inhibitor atorvastatin at the dose of 10 mg/day with simvastatin , lovastatin and pravastatin at doses of 10, 20 and 20 mg/day, respectively, and placebo, in type 2 diabetic patients with moderate elevation of LDL-cholesterol with or without elevation of triglycerides. All the quoted agents are enzyme inhibitors effective in lowering LDL-cholesterol in humans. The ef®cacy endpoints were the mean per cent changes in plasma LDL-cholesterol (primary), total cholesterol, triglycerides, and high-density lipoprotein (HDL)-cholesterol concentrations from baseline to the end of treatment (24 weeks). Atorvastatin at a dose of 10 mg/day produced: (1) a signi®cant reduction in LDL-cholesterol (± 37%) in comparison with equivalent doses of simvastatin (± 26%), pravastatin (± 23%), lovastatin (± 21%), and placebo (± 1%); (2) HDL-cholesterol increases (7.4%) comparable to or greater than those obtained with simvastatin (7.1%), pravastatin (3.2%), lovastatin (7.21%), and placebo (± 0.5%); (3) a signi®cantly greater reduction in total cholesterol (± 29%) than that obtained with simvastatin (± 21%), pravastain (± 16%), lovastatin (± 18%), and placebo (1%); and (4) a signi®cantly greater reduction in triglycerides than that obtained with all the other drugs and placebo. In all treatment groups no signi®cant variation in ®brinogen concentration was observed. All reductase inhibitors studied had similar levels of tolerance. There were no incidents of persistent elevations of serum aminotransferases or myositis.

An open-label follow-up study of low-to-intermediate dose testosterone replacement therapy (TRT) was conducted in 64 overweight patients (aged 65-75 years) with late onset hypogonadism (LOH) and increased fasting plasma glucose (FPG). Patients were subdivided into four treatment groups: oral testosterone (T) (T undecanoate, 80 mg/d), transmucosal T (60 mg/d), transdermal T (30 mg/d) or no treatment (control), and evaluated at 0 and 6 months. FPG, hemoglobin (Hb), prostate-specific antigen (PSA) and total T were measured and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated. Body mass index (BMI), waist circumference, fitness level (6-min walking test), Aging Males' Symptoms (AMS) scale, handgrip strength and energy expenditure with physical activity (Minnesota questionnaire for Leisure Time Physical Activity (LTPA)) were evaluated and a "frailty score" (based on: grip strength, gait speed and LTPA) was calculated. T levels increased in all treatment groups; the oral T group had values still in the hypogonadal range (5.9 ± 1.1 nmol/L). PSA and Hb concentrations did not change in any group. BMI, waist circumference, FPG and HOMA-IR improved in all T-treated groups after 6 months, with a greater effect seen with transmucosal and transdermal T compared with oral T. This study indicates that low-to-intermediate dose TRT may be safely utilized in LOH patients to ameliorate somatic and psychological frailty symptoms in association with improved anthropometric and glycometabolic parameters in aging, overweight men with LOH and impaired fasting glucose.

Thyroid function regulates lipid metabolism. Despite the fact that T2DM is more prevalent in the elderly, often associates with thyroid dysfunction and increases cardiovascular risk bothper seand via high TC and LDL-C levels, the association of the latter with FT3and FT4levels has not yet been fully investigated in T2DM. While trying to fill this gap in 296 elderly outpatients with T2DM, we found that TC and LDL-C correlated negatively with FT4and positively with FT3. When divided according to treatment by oral hypoglycaemic agents (OHA) and insulin (IT), they reacted differently with respect to investigated associations: in the OHA’s TC and LDL-C correlated negatively with FT4and showed no association with FT3, whereas, in the IT’s TC and LDL-C correlated positively with FT3and negatively with FT4. When controlled for possible confounding factors, these associations did not change in the IT’s but were missing in the OHA’s. Recent literature reports upon complex hypothalamic and peripheral interactions between T2DM and thyroid, and suggests T3to enhance cholesterol synthesis and to have a role in insulin resistance states. Further investigations are needed to understand the intimate mechanisms of lipid metabolism in T2DM with respect to thyroid function.

The time to achieve good metabolic control after diagnosis is essential for type 2 diabetes patients because it can influence long-term prognosis. This study aimed to elucidate the predictive role of several clinical and organization factors in normalizing metabolism within 6 months. A multi-centered, retrospective, observational study on 960 patients, with diabetes duration of 12 months or less, consecutively seen in 123 Italian clinics, was undertaken. Information about clinic's organization, along with data abstracted from medical records at enrollment (first visit) and after 6 months (follow-up visit), was collected. At 6 months, HbA1c dropped by -3.1 ± 2.2 points in those who achieved HbA1c

Aims Mediterranean-type diets reduce the risk of Type 2 diabetes. Whether a Mediterranean-type diet improves glycaemic control in diabetes remains unknown. Methods Weconducted a cross-sectional analysis in 901 outpatientswith Type 2 diabetes attending diabetes clinics located in Campania County, South Italy. We explored the relation between glycated haemoglobin (HbA1c), measured centrally, selfmeasured pre- and postprandial glucose levels and consumption of a Mediterranean-type diet. Adherence to a Mediterraneantype diet was assessed by a 9-point scale that incorporated the salient characteristics of this diet (range of scores, 0–9, with higher scores indicating greater adherence). The study was conducted from 2001 to 2007. Results Diabetic patients with the highest scores (6–9) had lower body mass index and waist circumferences, a lower prevalence of the metabolic syndrome and lower HbA1c and post-meal glucose levels than diabetic patients with the lowest scores (0–3). In multivariate analysis,meanHbA1c and 2-h post-meal glucose concentrations were significantly lower in diabetic patients with high adherence to a Mediterranean-type diet than those with low adherence [difference: HbA1c 0.9%, 95% confidence intervals (CI) 0.5–1.2%, P < 0.001; 2-h glucose 2.2 mmol ⁄ l, 95% CI 0.8–2.9 mmol⁄ l, P < 0.001]. Conclusions In Type 2 diabetes, greater adherence to a Mediterranean-type diet is associated with lower HbA1c and postprandial glucose levels. Diabet. Med. 26, 900–907 (2009) Keywords diet, glycaemic control, HbA1c, postprandial glucose, Type 2 diabetes Abbreviations BMI, body mass index; BMR, basal metabolic rate; CAPRI, Campanian Postprandial Hyperglycemia Study; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; MUFA, monounsaturated fatty acid; WHR, waist– hip ratio

Only few insulin-treated (IT) people with diabetes mellitus (DM) reach the target due to poor compliance and/or to sedentary lifestyle and/or to inadequate treatment regimen. The latter may be also brought about by often overlooked factors including insulin injection into altered skin areas, often brought about by incorrect habits, namely needle reutilization or poor compliance to the suggestion to continuously rotate skin injection areas. The aim of our study was to evaluate the rate of skin lesions within the sites commonly used for insulin injection in our IT DM patients and to verify whether a short-acting insulin analogue yielded different metabolic effects when injected in altered vs. normal skin areas. One hundred and eighty well-trained IT people with type 1 and type 2 DM (64 ± 15 years of age) consecutively referring to our unit underwent a standard clinical examination involving an accurate skin inspection protocol meant at looking for any alterations eventually affecting all possible injection sites, including bruising, multiple needle pricks and lipodystrophic nodules (LN). They were also tested for HPLC HbA1c determination and asked to fill in a standard questionnaire on injection habits. Furthermore, seven male, T1DM glulisine–glargine basal-bolus-treated patients in this group were randomly injected 10 IU glulisine into either normal skin (NS) or an LN by a nurse before a standard, 405 kcal breakfast, for blood glucose and free insulin determination at 0, 30, 45, 60, 75, 90, 120 and 150 min. More lesions were found in people over sixty (P\0.01) and in women (P\0.05). A higher prevalence of HbA1c[7.5% was found in patients with lesions (with an O.R. of 3.74) and further confirmed by data obtained from head-to-head comparison of insulin injection into an LN and NS. In fact, injection into an LN proved to impair and slow down insulin absorption, resulting in a higher absolute value and a larger variability of blood glucose levels than those observed by utilizing NS. This suggests us to pay more attention to all aspects of patient–team relationship to try and obtain good metabolic control in all people with diabetes and even more in the elderly.

The relationship between the vasodilating and the hyperbilirubinaemic effect of low and high doses (50 and 300 mg i.v.) of nicotinic acid was studied in baseline conditions and after indomethacin pretreatment in healthy controls and patients with Gilbert's syndrome (a condition characterized by fluctuating, nonhaemolytic unconjugated hyperbilirubinaemia). The hyperbilirubinaemic effect of nicotinic acid was confirmed to be more pronounced in Gilbert's syndrome patients than in controls. The magnitude of hyperbilirubinaemia in the two groups was not dependent on the dose of nicotinic acid or indomethacin pretreatment. A dose-dependent vasodilation which was inhibited by indomethacin could be demonstrated in both controls and Gilbert's syndrome subjects. Vasodilating properties of nicotinic acid were therefore found to be dissociated from the effect on bilirubin.

Wenying Yang and colleagues (October 18) report the fi ndings of a randomised controlled trial comparing acarbose with metformin as initial therapy for Chinese patients with newly diagnosed type 2 diabetes, showing similar tolerability and effi cacy. In addition to being the fi rst head-to-head comparison of metformin and acarbose as fi rst-line therapy for type 2 diabetes after failure of therapeutic lifestyle modifi cation, this intervention study is interesting as it is relevant to individualisation of pharmacological antidiabetic treatment in Asian adults with type 2 diabetes. Interest in personalised diabetes treatment is increasing. Personalised therapy involves an approach to clinical decisions that is applied to each individual patient and has, as a prerequisite, an accurate characterisation of that patient (phenotyping). Personalised therapy involves applying knowledge, scientifi c evidence, and common sense, and taking the realities of each individual patient’s circumstances into account. The fi nal aim is to optimise treatment responses, whilst similtaneously improving tolerability and compliance. To apply this in practice, physicians feel more comfortable having pragmatic aids such as predefi ned algorithms. Since 2010, the Italian Association of Diabetologists (Associazione Medici Diabetologi) has recognised the need to develop personalised treatment plans for patients with type 2 diabetes, taking into account the patient’s individual pattern of hyperglycaemia (phenotype), with the safest possible glycaemic control as a goal. Accordingly, tailored therapeutic algorithms have been developed for some of the most common type 2 diabetes phenotypes. These algorithms are available online in English, as a browser-operated interactive instrument. On the basis of a patient’s clinical features, the user can access a step-by-step suggested additive therapeutic approach. In fi ve of six Associazione Medici Diabetologi algorithms, alfa-glucosidase inhibitors are already considered as a fi rst pharmacological option for patients who are intolerant or have contraindications to metformin and who have predominantly postprandial hyperglycaemia. The study by Yang and colleagues shows that eastern Asian patients with newly diagnosed type 2 diabetes, a low BMI, a high dietary carbohydrate intake, and exaggerated postprandial glucose excursion can appropriately be treated with an alfa-glucosidase inhibitor as an alternative to metformin, at least in the short term, although cardiovascular eff ects of acarbose have yet to be investigated fully. This study, in our opinion, represents a creditable contribution and a step forward towards the development of population-specifi c and patho physiology-based treatment algorithms for type 2 diabetes.

We present the case of a 23-yr-old man who had had since birth marked and sustained unconjugated nonhemolytic hyperbilirubinemia and who had had several attacks of grand mal seizures. Analysis of serum bilirubin by diazoreactive methods showed serum levels of unconjugated bilirubin as high as 445 μmol/L that were not affected by phenobarbital administration. However, analysis of serum bile pigments by high-pressure liquid chromatography demonstrated marked decrease of unconjugated bilirubin after phenobarbital treatment (from 432.4 μmol/L to 291.0 μmol/L) associated with slight increase of bilirubin monoconjugates and diconjugates (from 0.25 μmol/L to 0.42 μmol/L). Furthermore, in the past few years the patient had exhibited striking skin hyperextensibity and diaphragm eventration. This case confirms that alkaline methanolysis—high-pressure liquid chromatography is the most reliable method for assessment of serum fraction bilirubin levels; that clinical parameters such as neurological signs do not unequivocally discriminate between type I and II Crigler-Najjar disease and that response to phenobarbital treatment remains the main diagnostic tool. (HEPATOLOGY 1991;13:213–215).

The effects of type 2 diabetes on evoked otoacoustic emissions (e-OAEs) elicited by clicks in subjects with normal hearing and the involvement of the central (CNS) and peripheral nervous system and acute hyperglycemia were investigated. In study 1, 110 type 2 diabetic patients and 106 control subjects matched for age and gender were investigated by e-OAEs. Central and peripheral neuropathy were evaluated respectively by auditory brainstem responses {ABRs) and according to San Antonio Consensus Conference criteria. In study 2, 10 healthy and 10 type 2 diabetic men matched for age, all with normal e-OAEs, underwent a 5-hour hyperglycemic clamp study, e-OAE tests were performed before and during the hyperglycemic clamp. In study 1, e-OAEs were impaired in 51.8% (57 of 110) of the diabetic subjects, in comparison to 4.7% (five of 106) of the control group (P < .0001). Diabetics with impaired e-OAEs (e-OAEs-), in comparison to those with normal e-OAEs (e-OAEs+), were older (51.0 _+5.8 v 45.1 +- 6.0 years, P < .001), had diabetes longer {11.5 -+ 4.4 v 7.0 +- 3.9 years, P < .001), achieved poorer metabolic control as judged by hemoglobin Alc ([HbAlc] 6.9% -+ 0.4% v 6.5% -+ 0.3%, P < .001), and had more peripheral neuropathy (46% v 23%, P < .02). No difference was observed between e-OAEs- and e-OAEs+ subjects for retinopathy or nephropathy. Nevertheless, when the duration of diabetes was corrected by multiple regression analysis, the correlation between sensorineural damage and peripheral neuropathy lost significance (P = .12). Diabetic groups (e-OAEs+ and e-OAEs-) showed greater latency in waves I, III, and V and greater interwave latency for waves I to V than the control group, but there was no significant difference in ABRs between e-OAEs+ and e-OAEs- subjects. In study 2, there were no significant changes in e-OAE intensities compared with basal values during the entire hyperglycemic clamp in either type 2 diabetic or control subjects. No difference was observed between the two groups at each time of the clamp. Thus, type 2 diabetic subjects show a higher rate of compromised e-OAEs than healthy individuals. The e-OAE dysfunction does not associate with either an injury to the auditory nervous pathway or diabetic microvasculopathy. The apparent interference of peripheral neuropathy in e-OAEs loses significance when corrected for the duration of diabetes.

Even though the association between liver cirrhosis and glucose tolerance alterations has been well documented, no data are available on the incidence of this association. In this paper we firstly report the results of a 4-year prospective longitudinal study performed on well-compensated cirrhotic patients with a normal glucose tolerance, in order to evaluate the incidence of glucose tolerance alterations with respect to liver efficiency during the time. The incidence of a diabetic response to a standard OGTT was 4.4% after a 1-year and 21.2% after a 4-year follow-up in stable cirrhotics. These figures are significantly higher than in the general population of our country. This large incidence was even significantly higher in cirrhotics with worsening liver efficiency at the end of the study (35.3%, P < 0.0001). Sex, family history of diabetes, alcoholic aetiology of the cirrhosis, and increment of portal hypertension do not seem to have any significant influence on the frequency of altered glucose tolerance. Therefore, we propose that liver cirrhosis and its worsening play a primary role as diabetogenic risk factors.

Sera from 46 newly diagnosed type 1 diabetic patients and from 100 normal controls were screened for ICA Cf ICA (standard immunofluorescence test) and for ICSA (ELISA assay) detection. Among 46 patients, 33 (71.7%) were ICA positive (16 of them also Cf ICA positive) and 21 resulted ICSA positive (45%). No correlation was found between ICSA, ICA and Cf ICA respectively. Therefore the ICSA detection, by a new and sensitive ELISA assay, in addition to ICA immunofluorescence determination, may be of significant diagnostic value in IDDM of recent onset.

Decreased fluidity of hepatocyte plasma membrane may contribute to the age-associated changes of liver function. This study aimed at investigating whether the hepatic clearance of organic anions declines with age and whether S-adenosylmethionine (SAMe), a substance proven to be effective in reversing the age-related decrease of membrane fluidity, might influence this process. Nicotinic acid (NA) half-life and serum bilirubin pharmacokinetics after NA load (5.9 mumol/kg body weight i.v.) were studied in 10 healthy young males (YM) aged 14-28 years and in 10 healthy elderly males (EM) aged 65-81 years, before and after SAMe administration (800 mg/day intravenously for 10 days). At baseline, EM showed serum total bilirubin (STB) levels significantly higher than YM. Similarly, the bilirubinaemic mean curves, STB peak and STB time curve concentration after NA load, expressed as area under the curve (AUC), were significantly higher in EM than in YM (p less than 0.01). NA half-life was also significantly prolonged in the aged group (p less than 0.001). SAMe treatment was followed by a significant decrease of basal STB, STB peak and AUC of STB after NA load in EM (p less than 0.01 vs pre-treatment values) while NA half-life was significantly shortened in both groups (p less than 0.001). As NA and bilirubin share a common carrier protein for hepatic uptake, bilitranslocase, the changes observed in EM may be attributed to the reduced lateral mobility of hepatocyte plasma membrane proteins occurring with age. SAMe, by improving membrane fluidity, may increase the diffusion coefficient of bilitranslocase restoring the hepatic handling of organic anions.

The plasma disappearance rate of sulfobromophthalein (VBSP; μmol/kg/min) was measured in 15 Gilbert's syndrome patients and 12 control subjects after intravenous injection of two different doses (0.59 and 5.90 μmol/kg) of the dye. Plasma disappearance rate was significantly reduced in Gilbert's syndrome patients after administration of 0.59 μmol sulfobromophthalein/kg (0.119 ± 0.016 vs. 0.146 ± 0.018 μmol/kg/min; mean ± S.D.; p < 0.001), whereas no difference was found with the higher dose (0.754 ± 0.040 vs. 0.767 ± 0.072 μmol/kg/min). Significant reduction was also found after administration to four Gilbert's syndrome patients and four control subjects of 0.29 and 2.95 μmol sulfobromophthalein (0.060 ± 0.005 μmol/kg/min vs. 0.077 ± 0.07 μmol/kg/min and 0.480 ± 0.012 μmol/kg/min vs. 0.591 ± 0.015 μmol/kg/min, respectively; p < 0.01). Competition studies with combined administration of sulfobromophthalein (0.59 μmol/kg) and different doses of rifamycin SV (0.59, 1.47 and 2.95 μmol/kg) showed a significant (p < 0.001) reduction in plasma disappearance rate in Gilbert's syndrome patients but not in controls. The rifamycin SV dose at which a 50% inhibition in plasma disappearance rate was observed was 0.8 μmol/kg. The apparent affinity (Km) of the hepatic transport was higher in Gilbert's syndrome patients than in control subjects (3.61 ± 0.37 μmol sulfobromophthalein/kg vs. 2.76 ± 0.29 μmol sulfobromophthalein/kg, mean ± S.D.; p < 0.01), whereas no difference was found in Vmax (0.95 ± 0.11 μmol sulfobromophthalein/kg vs. 0.93 ± 0.10 μmol sulfobromophthalein/kg/min, mean ± S.D.; N.S.). We conclude that a defective sulfobromophthalein hepatic transport is present in Gilbert's syndrome, and it may be revealed by lowering the does of the dye. The data sugest that the defect in Gilbert's syndrome is an impaired affinity for sulfobromophthalein of one or more of the putative transport proteins in the basolateral plasma membrane of the hepatocyte. (HEPATOLOGY 1990;12:213–217).

1. The plasma disappearance rate and the increment in plasma unconjugated bilirubin after intravenous administration of 5.9 μmol of rifamycin SV (RSV)/kg body wt. were investigated in 51 subjects with Gilbert's syndrome and 35 control subjects of both sexes. 2. Both the plasma disappearance rate and the unconjugated hyperbilirubinaemia after RSV administration were higher (P 3. In vitro, RSV was shown to inhibit sulphobromophthalein (BSP) uptake in rat liver plasma-membrane vesicles with a Ki of 20 μmol/l. Evidence that this effect was due to competition for bilitranslocase was sought on preparations of the purified protein. Under these experimental conditions, RSV inhibited BSP binding with a Ki of 17 μmol/l. 4. Since RSV competes with BSP for binding to bilitranslocase in vitro, the data are interpreted as suggesting that reduced bilitranslocase function might underlie the delayed RSV plasma clearance and the exacerbated unconjugated hyperbilirubinaemia present in Gilbert's syndrome.

In 9 healthy subjects we evaluated the effect of a constant ranitidine infusion (100 mg) on glucose (mg/dl), insulin (microU/ml) and C-peptide (ng/ml) serum levels promoted by oral glucose tolerance test (75 g). Ranitidine significantly increased the area under concentration/time curves for glucose and insulin but not that of C-peptide. Our data indicate that ranitidine does not affect pancreatic insulin release nor peripheral glucose utilization and are consistent with the hypothesis that ranitidine influences the hepatic clearance of glucose and insulin both of which undergo high first-pass liver extraction.

The bicompartmental kinetics of nicotinic acid (NA) and rifamycin-SV (R-SV)--2 organic anions that probably share a common hepatic uptake mechanism--were studied in 7 cases of Gilbert's syndrome (GS) and in 7 healthy controls matched for sex and age. In GS the NA and R-SV uptake constants (K21) were significantly decreased. In GS patients, simultaneous loads of NA and R-SV, the latter at increasing doses, produced: 1) a progressive lowering only of R-SV K21; and 2) an increase in R-SV hepatic plasma reflux (K12). Changes in biliary excretion ( Kee ) and hepatocellular pool (Ke) of both NA and R-SV probably depend on the rates of uptake and reflux constants of the two anions. The study of the parameters of compartmental kinetics of NA and R-SV confirms that the two organic anions, which have different metabolic routes and/or a different affinity for intracellular carriers, share common uptake mechanisms.

This study concerns the family of a girl affected by type 2 Crigler-Najjar syndrome; a brother and a sister died of kernicterus a few months after birth. The father and two living siblings had moderate unconjugated hyperbilirubinemia. The patient's liver uridine-diphospho-glucuronyl-transferase activity (UDPGT) was markedly reduced. All the family members underwent nicotinic acid (NA) load to test hepatic uptake capacity. This test, and NA half-life were normal in the patient and in her mother, and altered in the other relatives. The extent of the hyperbilirubinemic response to NA load, and of the NA half-life, together with physical examination over a one-year period were in good agreement with the diagnosis of Gilbert's syndrome in the patient's father and siblings. Our conclusion is that different impairments of hepatic handling of organic anions may be present in members of families with non-hemolytic bilirubinemia.

The clinical conditions due to damage to the peripheral sympathetic nervous system during diabetic neuropathy mainly involve alterations to subcutaneous vasomotility , temperature body regulation and exudation, which may take form of hyper or hypoactivity. Gustatory exudation and local anhydrosis are described in detail as well as the connection with aggravating factors like long duration, poor balance and early onset of diabetes mellitus . Change in the relevant cardiovascular reflexes, commonly used in diagnosing diabetic neuropathy, are also analysed with a discussion of their physiopathological background and clinical significance. Finally the painless infarct, sudden death and abnormal response to hypoglycaemia, that are the common features of diabetic neuropathy, are also described.

Patients with Gilbert's syndrome (GS) have impaired clearance by the liver of some organic anions. We looked for possible differences in hepatic clearance of nicotinic acid (NA) and rifamycin-SV (R-SV) among GS patients, and examined the effect produced by these anions on the plasma levels of unconjugated bilirubin (UCB). Two subgroups of GS patients, GS1 and GS2, were differentiated according to their ability to handle R-SV and NA. Compared with a control group, the alteration of the half-life both of NA and R-SV was less marked in GS1 than in GS2. UCB plasma concentration after NA and R-SV loading was more greatly increased in GS2 than in GS1 patients. In addition, a striking correlation was found in all subjects studied between UCB and the half-life of NA and R-SV. These related alterations of plasma UCB and plasma half-life or organic anions suggests a common defect of hepatic uptake. It is hypothesized that this defect is located at the level of a hepatic plasma membrane carrier.

Clinical symptoms and/or signs of peripheral neuropathy were found in 17 of the 19 patients we studied with liver cirrhosis. In 16 of the 19 patients electrophysiological abnormalities were also observed. Mild-moderate alterations involved both motor and sensory fibres, with a higher incidence in the lower rather than upper limbs, and indicated a fibre loss rather than a fibre demyelination. These changes were observed in both alcoholic and non-alcoholic cirrhotics, suggesting a primary role of liver cirrhosis per se. In fact, both the clinical and electrophysiological abnormalities were related to the severity of the liver disease. A careful clinical examination could reveal the presence and extent of neuropathy in most cirrhotic patients.

The serum increments in unconjugated bilirubin and total iron were determined after intravenous administration of 5.90 mumol/kg body weight of nicotinic acid (NA) in 26 patients with Gilbert's syndrome (GS), seven patients with hemolytic anemia, and 13 healthy volunteers. The hyperbilirubinemic response, expressed as the area under time concentration curve of unconjugated bilirubin (AUCBR, milligrams per deciliter per 240 minutes) was significantly higher (P less than 0.01) in patients with GS than in controls and patients with hemolytic anemia, in whom no difference was observed. In contrast, comparable values of the hypersideremic effect (AUCFe, milligrams per deciliter per 240 minutes) were noticed among the three groups. In seven consecutive patients with GS, seven with hemolytic anemia, and four healthy volunteers, AUCBR, AUCFe, and the NA plasma half-life of the first fast slope of the curve were determined at three different doses of the drug (1.18, 2.95, and 5.90 mumol NA per kilogram body weight). A significant, dose-dependent increase in AUCBR was present in patients with GS, whereas it remained constant both in controls and in patients with hemolytic anemia. The NA plasma half-life was also significantly prolonged in GS with each of the three doses, but remained unchanged in the other two groups. In patients with GS, a linear correlation (r = 0.891, P less than 0.001) was present between AUCBR and NA plasma half-life. In contrast, the AUCFe value remained constant at the different doses used in the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The hyperbilirubinemia induced by nicotinic acid (NA) is well correlated to 14C-bilirubin clearance, and is utilized to diagnose Gilbert's syndrome (GS). However, NA produces a number of vascular prostaglandin-mediated side effects. In an attempt to improve the NA test we evaluated the influence of pretreatment with Indomethacin, a PG-synthetase inhibitor, both on side effects and hyperbilirubinemia. NA (5.9 mumoles/kg of body weight i.v.) was administered on two separate occasions, before and one hour after i.m. injection of 100 mg Indomethacin in 11 GS males and 11 controls matched for sex and age (age range 18.34 years). The hyperbilirubinemic effect of NA was not modified by Indomethacin in any subject; the side effects were either significantly reduced or completely abolished. We suggest that patients undergoing the NA test for the diagnosis of GS be pretreated with Indomethacin.

Diabetic patients often suffer from symptoms arising from the gastrointestinal tract. Several factors are considered responsible for these alterations, including abnormalities of gastric motility. Recently Helicobacter pylori (HP) has been identified in a relevant aliquot of subjects with or without gastrointestinal abnormalities, but only scarce and controversial data are available on the prevalence of HP and the association between HP and chronic gastritis or peptic ulcer in diabetic patients. In addition, the possible association between alterations of gastric motility induced by autonomic neuropathy (AN) and the presence of HP has never been evaluated in diabetic subjects. In this study we document the presence of HP in the gastric biopsies of 73% out of a series of 29 patients affected by type 2 diabetes and non-ulcer dyspepsia (3 with oesophagitis, 10 with gastritis, 7 with bulbar duodenitis, and 9 with a normal endoscopy), with a significantly higher prevalence (P < 0.01) in subjects with AN (74%) than in subjects without AN (26%). Two other tests have been compared with the histological evidence of HP (used as golden standard), i.e. the urease test (CP-test) and the assay of anti-HP G-immunoglobulins, both of which were positive in a significantly (P < 0.01) higher percentage of neuropathic patients in comparison with non-neuropathic patients. The sensitivity and the specificity of the CP-test were 96% and 100%, respectively. Similarly, both the sensitivity and the specificity of the assay of IgG HP-Ab were 100%. Since patients affected by non-ulcer dyspepsia and NIDDM complicated by autonomic neuropathy are under a higher risk to be carriers of HP than non-neuropathic or non-diabetic patients. The assay of serum IgG HP-Ab could be used as a screening method, thus avoiding the more expensive and time-consuming endoscopy.