Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

The evaluation of tactile dysfunction in the hand in type 1 diabetes: a novel method based on haptics.

AIMS: We present an innovative method based on haptics for the evaluation of the sense of touch in the hand, in people affected by type 1 diabetes. METHODS: Forty individuals affected by diabetes and 20 healthy controls took part in the study; the diabetes group was further divided into two subgroups based on vibration sensitivity in the lower limb. By means of a novel haptic device, tactile sensitivity in the fingertip was measured as the ability of the participants to discriminate slip motion speed. RESULTS: Tactile sensitivity was significantly lower in individuals affected by diabetes as compared to controls. Depending on the subgroup, the difference from the controls was equal to 0.11 (95% CI from 0.029 to 0.186) and to 0.267 (95% CI from 0.198 to 0.336). Within the diabetes group, tactile sensitivity correlated with vibration sensitivity in the upper (p = 0.001) and lower limb (p = 0.003). A significant relationship between nerve conduction parameters and tactile sensitivity was found (p = 0.03). Finally, we combined the different predictors (clinical, vibratory and electroneurography data) by using cluster analysis; tactile sensitivity was found to be significantly different between different clusters (p = 0.004). CONCLUSIONS: Early signs of tactile dysfunction in the hand were found in individuals affected by diabetes, even in absence of diabetic neuropathy. The protocol presented in this study is a promising tool for the assessment of tactile dysfunction in the hand in people affected by type 1 diabetes.

Outer retina dysfunction and choriocapillaris impairment in type 1 diabetes.

To study the outer retina morpho-functional characteristics and the choriocapillaris (CC) features in type 1 diabetic (T1D) patients, with and without signs of diabetic retinopathy (NPDR and NoDR). Twenty-five NPDR and 18 NoDR eyes were imaged by Optical Coherence Tomography Angiography. Ellipsoid zone (EZ) "normalized" reflectivity and CC perfusion density parameters, as flow deficits number (FDn), flow deficit average area (FDa) and flow deficit percentage (FD%), were analysed. Multifocal electroretinogram (mfERG) response amplitude densities (RADs) were measured. Mean EZ "normalized" reflectivity, CC FDn and FD% values, were similar (p > 0.05) in both groups, FDa was significant greater (p > 0.05) in NPDR compared with NoDR eyes. MfERG-RADs were similar in both groups. NPDR eyes showed a significant (p < 0.05) linear correlation between RADs and both, CC FDa and FD%. The EZ "normalized" reflectivity was negatively correlated with CC FD% in NoDR eyes. In NPDR T1D eyes a significant relationship between abnormal outer retina functional responses and CC impairment was observed, while in NoDR eyes the photoreceptor reflectivity was correlated to CC abnormalities. The outer retina dysfunction in NPDR correlated to CC drop-out let hypothesize that the outer retinal elements are functionally impaired in proportion to the CC vascular supply deficit.

The use of real time continuous glucose monitoring or flash glucose monitoring in the management of diabetes: A consensus view of Italian diabetes experts using the Delphi method.

Until recently, in Italy, the use of continuous glucose monitoring (CGM) systems has been limited, but is now rapidly increasing, including the so-called real-time CGM (rtCGM) and the intermittently viewed CGM (iCGM), also called Flash Glucose Monitoring (FGM). These technologies overcome many of the limitations of self-monitoring of blood glucose (SMBG) by fingerprick and allow to go beyond HbA1c to check glucose control in diabetes. However, standardized protocols for applying and interpreting rtCGM and FGM data are lacking. In this paper, we delineate a consensus amongst Italian diabetes physicians on the attributes of rtCGM and FGM technologies, and introduce a consistent approach for their use by Italian healthcare professionals. Most experts consider rtCGM and FGM as two separate categories of interstitial subcutaneous fluid (ISF) sensing technologies, and see them as superior to SMBG. Furthermore, there is strong consensus that rtCGM and FGM reduce hypoglycemia risk, increase the amount of time in the target glucose range and augment treatment satisfaction. However, there is still no agreement on the indication of the FGM for subjects who suffer asymptomatic hypoglycemia. Consensus on the role of education in initiating and optimizing use of rtCGM/FGM and about the interpretation of glucose trends was near unanimous, whereas no consensus was reached on the statement that there are no disadvantages/risks of rtCGM/FGM. Some issues remain in rtCGM/FGM management: a) risk of excessive correction of high or low glucose; b) risk of alert fatigue leading to alert silencing or rtCGM termination; c) allergic reaction to the adhesive keeping rtCGM or FGM sensors in place. The panel almost unanimously agreed that sensor accuracy depends on multiple variables, that alarm setting should be individualized, and that global glycemic profile represent an useful tool in interpreting glucose data. More clinical studies and a wider use of these devices will increase the efficacy and effectiveness of continuous glucose monitoring in Italy.

Predictors of treatment response to liraglutide in type 2 diabetes in a real-world setting.

AIMS: There is an unmet need among healthcare providers to identify subgroups of patients with type 2 diabetes who are most likely to respond to treatment. METHODS: Data were taken from electronic medical records of participants of an observational, retrospective study in Italy. We used logistic regression models to assess the odds of achieving glycated haemoglobin (HbA1c) reduction ≥ 1.0% point after 12-month treatment with liraglutide (primary endpoint), according to various patient-related factors. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify distinct homogeneous patient subgroups with different odds of achieving the primary endpoint. RESULTS: Data from 1325 patients were included, of which 577 (43.5%) achieved HbA1c reduction ≥ 1.0% point (10.9 mmol/mol) after 12 months. Logistic regression showed that for each additional 1% HbA1c at baseline, the odds of reaching this endpoint were increased 3.5 times (95% CI: 2.90-4.32). By use of RECPAM analysis, five distinct responder subgroups were identified, with baseline HbA1c and diabetes duration as the two splitting variables. Patients in the most poorly controlled subgroup (RECPAM Class 1, mean baseline HbA1c > 9.1% [76 mmol/mol]) had a 28-fold higher odds of reaching the endpoint versus patients in the best-controlled group (mean baseline HbA1c ≤ 7.5% [58 mmol/mol]). Mean HbA1c reduction from baseline was as large as - 2.2% (24 mol/mol) in the former versus - 0.1% (1.1 mmol/mol) in the latter. Mean weight reduction ranged from 2.5 to 4.3 kg across RECPAM subgroups. CONCLUSIONS: Glycaemic response to liraglutide is largely driven by baseline HbA1c levels and, to a lesser extent, by diabetes duration.

The ideal blood pressure target to prevent cardiovascular disease in type 2 diabetes: a neutral viewpoint.

Type 2 diabetes mellitus (T2DM) and essential hypertension are often associated, and retrospective data analyses suggest an association between lower blood pressure (BP) values and lower cardiovascular (CV) risk in patients with T2DM. However, the most recent intervention trials fail to demonstrate a further CV risk reduction, for BP levels <130/80 mm Hg, when compared to levels <140/90 mm Hg. Moreover, a J-shaped, rather than a linear, relationship of BP reduction with incident CV events has been strongly suggested. We here debate the main available evidences for and against the concept of 'the lower the better', in the light of the main intervention trials and meta-analyses, with a particular emphasis on the targets to be pursued in elderly patients. Finally, the most recent guidelines of the scientific societies are critically discussed.

Acute caloric restriction improves glomerular filtration rate in patients with morbid obesity and type 2 diabetes.

AIM: The role of caloric restriction in the improvement of renal function following bariatric surgery is still unclear; with some evidence showing that calorie restriction can reduce proteinuria. However, data on the impact of caloric restriction on renal function are still lacking. METHODS: Renal function, as measured by glomerular filtration rate (GFR), was evaluated in 14 patients with type 2 diabetes mellitus, morbid obesity and stage 2 chronic kidney disease before and after a 7-day very low-calory diet (VLCD). RESULTS: After the VLCD, both GFR and overall glucose disposal (M value) significantly increased from 72.6 ± 3.8 mL/min/1.73 m(-2) BSA to 86.9 ± 6.1 mL/min/1.73 m(-2) BSA (P=0.026) and from 979 ± 107 µmol/min(1)/m(2) BSA to 1205 ± 94 µmol/min(1)/m(2) BSA (P=0.008), respectively. A significant correlation was observed between the increase in GFR and the rise in M value (r=0.625, P=0.017). CONCLUSION: Our observation of improved renal function following acute caloric restriction before weight loss became relevant suggesting that calory restriction per se is able to affect renal function.

Insulin sensitivity, and ß-cell function in relation to hemoglobin A1C.

BACKGROUND AND AIMS: The A1C diagnostic criterion for identifying individuals at increased risk for diabetes, introduced by the American Diabetes Association in 2010, was not defined on the basis of the principal pathophysiological abnormalities responsible for the development and progression of type 2 diabetes; we therefore wished to gain a deeper insight into the metabolic abnormalities characterizing the group of at risk individuals with an A1C value of 5.7-6.4%. METHODS AND RESULTS: As many as 338 non-diabetic offspring of type 2 diabetic patients were consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT), and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp. As compared with subjects with A1C <5.7%, individuals with A1C of 5.7-6.4% exhibited lower insulin sensitivity after adjusting for age, gender and body mass index (BMI). Insulin secretion estimated from the OGTT, did not differ between the two groups. By contrast, as compared with subjects with A1C <5.7%, the acute insulin response (AIR) during an IVGTT and both IVGTT-derived and OGTT-derived disposition indexes were reduced in individuals with A1C of 5.7-6.4% after adjusting for age, gender and BMI. As A1C increased to ≥ 5.7%, a sharp decrease in insulin sensitivity and ß-cell function, measured as disposition index, was observed. CONCLUSIONS: Caucasian individuals with A1C ≥ 5.7% exhibit both core pathophysiological defects of type 2 diabetes i.e. insulin resistance and ß-cell dysfunction.

Rapid and easy assessment of insulin resistance contributes to early detection of polycystic ovary syndrome.

AIMS: Polycystic ovary syndrome (PCOS) is frequently observed in women of reproductive age, and is associated with disturbances in both reproductive and metabolic function. Insulin resistance (IR) is key to the pathophysiology of PCOS, and early detection may improve outcomes in this patient group. Rapid and straightforward laboratory tests may contribute towards early detection. METHODS: A retrospective chart review of 185 women presenting for the first time to a gynecology clinic was carried out. Of this group, 77 met the inclusion criteria. The sample was divided according to insulin sensitivity (IS) given by the Matsuda Index, and the two groups were compared using correlation analysis. Furthermore, the sensitivity and specificity of the Matsuda, homeostasis model assessment of IR (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) indexes were compared. RESULTS: Although bodu mass index (BMI) was higher in the insulin resistant group than the insulin sensitive group, the mean age of the IR group was actually lower. HOMA-IR and QUICKI correlated well with the Matsuda index in both groups. The HOMA-IR test showed the highest sensitivity and specificity in the detection of IR when compared to the Matsuda Index, and no added benefit was derived from using a combination of both QUICKI and HOMA- 1R. CONCLUSIONS: In a group of 77 women diagnosed with PCOS, 49 (63.6%) had IR according to the Matsuda index. The HOMA-IR index, which is based on fasting serum insulin and glucose, correlated closely with the Matsuda index, indicating it may be a reliable substitute in the detection and subsequent early intervention required to improve outcomes in PCOS.

Impact of glycemic variability on cardiovascular outcomes beyond glycated hemoglobin. Evidence and clinical perspectives.

AIMS: The aim of this review is to focus on intra-day glucose variability (GV), specifically reviewing its correlation with HbA1c, the methods currently available to measure it, and finally the relationship between GV and cardiovascular outcomes, in type 1 and type 2 diabetic patients, and in the non-diabetic population. DATA SYNTHESIS: The term GV has been used in the literature to express many different concepts; in the present review, we focus our attention on intra-day GV. In particular, we try to assess whether GV provides additional information on glycemic control beyond HbA1c, since GV seems to be incompletely expressed by HbA1c, particularly in patients with good metabolic control. Many different indexes have been proposed to measure GV, however at the moment no "gold standard" procedure is available. Evidence in vitro, in experimental settings and in animal studies, shows that fluctuating glucose levels display a more deleterious effect than constantly high glucose exposure. However, these findings are not completely reproducible in human settings. Moreover, the relationship between GV and cardiovascular events is still controversial. CONCLUSIONS: The term GV should be reserved to indicate intra-day variability and different indexes of GV should be used, depending on the metabolic profile of the population studied and the specific issue to be investigated. Self glucose monitoring or continuous glucose monitoring should be used for assessing glucose variability.

Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction in patients with diabetes.

There are substantial advances in understanding disordered gastrointestinal autonomic dysfunction in diabetes. It occurs frequently. The underlying pathogenesis is complex involving defects in multiple interacting cell types of the myenteric plexus as well. These defects may be irreversible or reversible. Gastrointestinal symptoms represent a major and generally underestimated source of morbidity for escalating health care costs in diabetes. Acute changes in glycaemia are both determinants and consequences of altered gastrointestinal motility. 35-90% of diabetic men have moderate-to-severe erectile dysfunction (ED). ED shares common risk factors with CVD. Diagnosis is based on medical/sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to patient's complaints and risk factors. Treatment is based on PDE5-inhibitors (PDE5-I). Other explorations may be useful in patients who do not respond to PDE5-I. Patients at high cardiovascular risk should be stabilized by their cardiologists before sexual activity is considered or ED treatment is recommended. Estimates on bladder dysfunction prevalence are 43-87% of type 1 and 25% of type 2 diabetic patients, respectively. Common symptoms include dysuria, frequency, urgency, nocturia and incomplete bladder emptying. Diagnosis should use validated questionnaire for lower urinary tract symptoms. The type of bladder dysfunction is readily characterized with complete urodynamic testing. Sudomotor dysfunction is a cause of dry skin and is associated with foot ulcerations. Sudomotor function can be assessed by thermoregulatory sweat testing, quantitative sudomotor axon reflex test, sympathetic skin response, quantitative direct/indirect axon reflex testing and the indicator plaster.

Metabolic syndrome in subjects at high risk for type 2 diabetes: the genetic, physiopathology and evolution of type 2 diabetes (GENFIEV) study.

BACKGROUND AND AIM: We evaluated the relationship between insulin resistance (IR) and insulin secretion with the metabolic syndrome (MS) in 885 subjects (377 men/508 women, age 49±11 years, BMI 29±5.2kgm(-2)) at risk of diabetes enrolled in the genetics, pathophysiology and evolution of type 2 diabetes (GENFIEV) study. METHODS AND RESULTS: All subjects underwent a 75-g oral glucose tolerance test (OGTT) for the estimation of plasma levels of glucose and C-peptide, as well as fasting insulin and lipid profile. IR was arbitrarily defined as HOMA-IR value above the 75th centile of normal glucose tolerance (NGT) subjects. Overall MS prevalence (National Cholesterol Treatment Panel-Adult Treatment Panel (NCEP-ATPIII) criteria) was 33%, 19% in subjects with NGT, 42% in impaired fasting glucose (IFG), 34% in impaired glucose tolerance (IGT), 74% in IFG+IGT subjects, and 56% in newly diagnosed diabetic patients. Prevalence was slightly higher with IDF criteria. MS prevalence was >50% in subjects with 2h glucose >7.8mmoll(-1), independently of fasting plasma glucose. IR prevalence was higher in subjects with MS than in those without (63% vs. 23%; p<0.0001) and increased from 54% to 73% and 88% in the presence of three, four or five traits, respectively. IR occurred in 42% of subjects with non-diabetic alterations of glucose homeostasis, being the highest in those with IFG+IGT (IFG+IGT 53%, IFG 45%, IGT 38%; p<0.0001). Individuals with MS were more IR irrespective of glucose tolerance (p<0.0001) with no difference in insulinogenic index. Hypertriglyceridaemia (OR: 3.38; Confidence Interval, CI: 2.294.99), abdominal obesity (3.26; CI: 2.18-4.89), hyperglycaemia (3.02; CI: 1.80-5.07) and hypertension (1.69; CI: 1.12-2.55) were all associated with IR. CONCLUSIONS: These results show that in subjects with altered glucose tolerance (in particular IFG+IGT) MS prevalence is high and is generally associated to IR. Some combinations of traits of MS may significantly contribute to identify subjects with IR.

Highlights from "Italian Standards of care for Diabetes Mellitus 2009-2010".

The Italian Standards for the Treatment of Diabetes Mellitus represent a consensus document of the two Italian scientific diabetes societies (AMD and SID), providing specific recommendations for the diagnosis and treatment of diabetes and its complications. The level of scientific evidence behind every recommendation has been classified in accordance with the National Guidelines Plan. An original processing system was employed: the document prepared by the Editorial Team was published online for 20 days, and the suggestions and criticisms of about 30 persons were evaluated and integrated to those provided by a panel of diabetologists and members of other healthcare professions dedicated to diabetes care, as well as lay members. Lastly, the document was approved by AMD and SID National Steering Committees. In this version, some highlights of the full document (www.siditalia.it; www.aemmedi.it) concerning the main and most representative recommendations on diagnosis and treatment of diabetes and its complications as well as on diabetes care in some specific contexts, are reported.

Hyperinsulinaemia in offspring of Type 2 diabetic patients: impaired response of carbohydrate metabolism, but preserved cardiovascular response.

AIMS: To investigate the effects of endogenous insulin on haemodynamics in nine offspring of Type 2 diabetic patients (P), compared with 18 subjects without family history of diabetes (C), all with normal glucose tolerance. METHODS: All subjects underwent a 180-min oral glucose tolerance test with continuous blood pressure and ECG recording. Low-to-high frequency ratio (LF/HF), an index of the sympatho-vagal balance, was calculated by heart rate spectral analysis. RESULTS: At baseline, LF/HF correlated with fasting plasma insulin (r = 0.44, P < 0.03) and with insulin/glucose ratio (r = 0.46, P < 0.03). Plasma insulin, basally similar in the two groups, was significantly increased in P (342 +/- 34.2) when compared to C (177.6 +/- 25.2 pmol/l), P < 0.005 from time 30min onward. Blood glucose, also similar at baseline, remained not significantly different in P (5.74 +/- 0.25) vs. C (5.08 +/- 0.27 mmol/l), throughout the study. Diastolic blood pressure significantly decreased in P, but not in C during the first hour of the study. Finally, LF/HF ratio significantly increased in P (2.5 +/- 0.4 vs. C, 1.7 +/- 0.2) during the first hour. CONCLUSIONS: In conclusion, the offspring of Type 2 diabetic patients with normal glucose tolerance display an increased insulin secretion; however, they are not resistant to the haemodynamic effects of insulin, as suggested by the reduction of diastolic blood pressure. This, in turn, may determine a chronic sympathetic activation, which could be involved in the pathogenesis of Type 2 diabetes mellitus.

Assessment of sympathetic innervation of the heart in diabetes mellitus using 123I-MIBG.

Radio-labeled metaiodobenzylguanidine (MIBG) is considered an established sympathetic neuron imaging agent capable of scintigraphically visualizing the organs richly innervated by the sympathetic nervous system. Its clinical applications now include cardiac and pulmonary adrenergic imaging. The quantitative determination of global and/or regional abnormalities of MIBG heart uptake has been demonstrated to be very useful in several clinical settings representing one of the major determinants of adverse prognosis. The presence and the severity of autonomic neuropathy are known as important prognostic factors in patients with diabetes. MIBG scintigraphy is able to non-invasively assess and characterize the adrenergic abnormalities of the cardiac innervation also in these patients. In order to evaluate whether 123I-MIBG is able to reveal abnormalities of myocardial adrenergic function in different groups of diabetic patients, we performed 123I-MIBG scintigraphy in control subjects and in normotensive Type 1 diabetic patients with and without autonomic neuropathy (N+ and N- patients), selected according to results of cardiovascular reflex tests. Regional abnormalities of adrenergic innervation were revealed in 10% of control subjects, in 70% of N- patients and in 100% of N+ patients. The finding of a higher than expected prevalence of MIBG regional abnormalities in patients without signs or symptoms of autonomic neuropathy allows to hypothesize that cardiac autonomic nervous damage occurs earlier than previously known in diabetic patients whose cardiovascular tests are still completely normal.

Effects of beta-adrenergic blockade on insulin-mediated glucose disposal in hypertensive and normotensive rats.

OBJECTIVE: To evaluate the impact of beta-adrenergic blockade in spontaneously hypertensive rats (SHR) and in their normotensive controls, Wistar-Kyoto (WKY) rats, on whole-body glucose disposal under metabolic steady state conditions, in unrestrained and conscious animals. METHOD: SHR (n = 13) and WKY rats (n = 12) underwent a 240 min insulinaemic clamp study with or without a super-infusion (120th to 240th minutes; second step) of propranolol. RESULTS: From 0 to 120 min (the first step) SHR showed significantly increased glucose uptake, muscle glycogen synthesis and glycogen synthase activity compared with WKY rats. When propranolol was superinfused, glucose uptake and muscle glycogen synthesis in SHR returned to levels similar to those observed in WKY rats during the first step. No significant differences were found for whole-body glycolysis in SHR and WKY in the first and second steps. CONCLUSION: Hypertensive rats display an increased insulin sensitivity compared with controls. Beta-Blockade is associated with a reduction in overall glucose metabolism in SHR, but not in WKY rats.

Effects of insulin on cholesterol synthesis in type II diabetes patients.

OBJECTIVE: To evaluate the effects of intensive insulin therapy and subsequent optimized metabolic control on daily urinary mevalonic acid (MVA) excretion, an index of whole-body cholesterol synthesis, and the acute effects of insulin on plasma MVA concentrations in type II diabetes. RESEARCH DESIGN AND METHODS: Ten (five men and five postmenopausal women) nonobese, normolipidemic (total cholesterol < 6.2 mmol/l, triglycerides < 2.82 mmol/l), type II diabetic patients in poor metabolic control (HbA1c > 10%, fasting plasma glucose > 11 mmol/l) and receiving sulfonylurea treatment were selected. The 24-h urinary MVA excretion and plasma lipid values were determined before and after intensive insulin therapy. The acute effects of insulin on plasma MVA concentrations were also evaluated during a 3-h euglycemic hyperinsulinemic clamp study. RESULTS: Urinary MVA excretion rates (mumol/24h) were 1.82 +/- 0.21 in control subjects and 2.49 +/- 0.35 (P < 0.01 vs. control subjects) and 1.78 +/- 0.28 in patients before and after intensive insulin therapy, respectively. Total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides decreased by 9, 8, and 12%, respectively, after blood glucose optimization. Acute insulin infusion during the euglycemic clamp studies reduced mean plasma MVA concentrations at 120 and 180 min by 29 and 38%, respectively (P < 0.01 for both vs. baseline). CONCLUSIONS: Our study demonstrates that in nonobese, normolipidemic, type II diabetic patients under poor metabolic control, an increased cholesterol synthesis is normalized by insulin therapy. Hyperinsulinemia in the presence of euglycemia acutely decreases the circulating levels of MVA, the immediate product of hydroxymethylglutaryl-CoA reductase activity and an index of whole-body cholesterol synthesis.

Glycogen synthase activity in two rat models of hypertension.

Several studies on both humans and animal models have reported a pathogenetic relationship among hyperinsulinism, insulin resistance, and hypertension. We have previously evaluated whole body glucose disposal and insulin sensitivity in different models of hypertensive rats, showing an increase rather than an impairment of glucose metabolism, which in turn was due to an improved ability of insulin to channel the absorbed glucose towards the nonoxidative disposal. Aiming to confirm our previous findings we performed the direct assay of skeletal muscle glycogen synthase on tissue samples from the previous clamp studies, as a rate limiting step enzyme of glycogen synthesis, under conditions of physiologic hyperinsulinemia and euglycemia. Glycogen synthase was assayed on samples from rectus muscle tissues of spontaneously hypertensive rats and high sodium, one kidney, one figure-8 hypertensive rats. Compared to controls, our data show an increased activity of glycogen synthase in the hypertensive animals, which is consistent with the increased glycogen synthesis previously reported. In conclusion, under our experimental conditions, hypertension and chronic hyperadrenergism are associated with an increased ability of insulin to stimulate glucose uptake and disposal. These latter effects are mainly due to an increase in nonoxidative disposal and glycogen synthase activity.

Relationship between autonomic neuropathy, 24-h blood pressure profile, and nephropathy in normotensive IDDM patients.

OBJECTIVE: To evaluate the relationship between autonomic neuropathy, nephropathy, and 24-h blood pressure (BP) pattern in insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: We studied 30 normotensive IDDM patients without overt nephropathy, divided into two groups and matched for age, duration of diabetes, and HbA1, according to the presence of cardiovascular autonomic neuropathy. We simultaneously measured 24-h BP and urinary albumin excretion rate (UAE) on urine collections timed overnight and at 2-h intervals during the day. RESULTS: Mean day and night systolic and diastolic BP values did not significantly differ between the groups. Mean night albuminuria was significantly higher in patients with autonomic neuropathy than in those without (61.4 +/- 104.6 [mean +/- SD] vs. 16 +/- 25.2 micrograms/min, P < 0.04). The percentages day-night changes in systolic BP, diastolic BP, and UAE were significantly lower in neuropathic patients (systolic BP: 2.4 +/- 7.7 vs. 9.6 +/- 4.2%, P < 0.001; diastolic BP: 8.4 +/- 6.9 vs. 15.5 +/- 5.4%, P < 0.002; UAE: -8 +/- 99.4 vs. 49.3 +/- 29.4%, P < 0.02) and were inversely related to autonomic score, index of autonomic neuropathy degree (r = -0.54, P < 0.002; r = -0.58, P < 0.001; and r = -0.53, P < 0.005, respectively). In patients with autonomic neuropathy, 2-h day periods and day and night UAE were more strongly related, respectively, to mean 2-h day periods (r = 0.58, P < 0.0001), day systolic BP (r = 0.67, P < 0.04), and night systolic BP (r = 0.69, P < 0.04) than in patients without autonomic neuropathy (2-h day periods: r = 0.32, P < 0.001; day: r = 0.37, NS; night: r = 0.35, NS). CONCLUSIONS: Autonomic neuropathy in IDDM patients is associated with reduced nocturnal falls in BP and UAE and with a stronger relationship of UAE to systolic BP. We suggest a pathogenetic role of autonomic neuropathy in the development of diabetic nephropathy through changes in nocturnal glomerular function and by enhanced kidney vulnerability to hemodynamic effects of BP.

The effects of insulin on plasma mevalonate concentrations in man.

Mevalonate production is a limiting step in cholesterol synthesis. We studied the effects of insulin on plasma mevalonate concentrations during a 3-hour euglycemic hyperinsulinemic clamp study in 10 healthy males starting at 9 h a.m. after 14 h of fasting. Physiological variations in plasma mevalonate were evaluated on a different day from 9 to 12 h a.m. under saline infusion. During the clamp studies, slight but significant decreases were noted for VLDL-triglyceride and VLDL-cholesterol at 120 and 180 min (p < 0.05) and for apolipoprotein B-100 from 60 min on (p < 0.05). Plasma mevalonate decreased significantly by 34 and 41% at 120 and 180 min, respectively (p < 0.001), while the mean percent decrease due to diurnal variations was 12% at 12 h a.m. In conclusion, hyperinsulinemia in the presence of euglycemia acutely decreases the circulating levels of mevalonic acid, the immediate product of HMG CoA reductase in the cholesterol pathway.