Ilaria Giordani

Impact of Glycemic and Blood Pressure Variability on Surrogate Measures of Cardiovascular Outcomes in Type 2 Diabetic Patients

OBJECTIVE The effect of glycemic variability (GV) on cardiovascular risk has not been fully clarified in type 2 diabetes. We evaluated the effect of GV, blood pressure (BP), and oxidative stress on intima-media thickness (IMT), left ventricular mass index (LVMI), flow-mediated dilation (FMD), and sympathovagal balance (low frequency [LF]/high frequency [HF] ratio) in 26 type 2 diabetic patients (diabetes duration 4.41 ± 4.81 years; HbA1c 6.70 ± 1.25%) receiving diet and/or metformin treatment, with no hypotensive treatment or complications. RESEARCH DESIGN AND METHODS Continuous glucose monitoring (CGM) data were used to calculate mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA)-2, mean blood glucose (MBG), mean postprandial glucose excursion (MPPGE), and incremental area under the curve (IAUC). Blood pressure (BP), circadian rhythm, and urinary 15-F2t-isoprostane (8-iso-prostaglandin F2α [PGF2α]) were also evaluated. Subjects were divided into dipper (D) and nondipper (ND) groups according to ΔBP. RESULTS IMT and LVMI were increased in ND versus D (0.77 ± 0.08 vs. 0.68 ± 0.13 [P = 0.04] and 67 ± 14 vs. 55 ± 11 [P = 0.03], respectively). MBG, MAGE, and IAUC were significantly associated with LF/HF ratio at night (r = 0.50, P = 0.01; r = 0.40, P = 0.04; r = 0.41, P = 0.04, respectively), MPPGE was negatively associated with FMD (r = −0.45, P = 0.02), and CONGA-2 was positively associated with LVMI (r = 0.55, P = 0.006). The Δsystolic BP was negatively associated with IMT (r = −0.43, P = 0.03) and with LVMI (r = −0.52, P = 0.01). Urinary 8-iso-PGF2α was positively associated with LVMI (r = 0.68 P < 0.001). CONCLUSIONS An impaired GV and BP variability is associated with endothelial and cardiovascular damage in short-term diabetic patients with optimal metabolic control. Oxidative stress is the only independent predictor of increased LV mass and correlates with glucose and BP variability.

Very-low-calorie diet: a quick therapeutic tool to improve β cell function in morbidly obese patients with type 2 diabetes

BACKGROUND Caloric restriction in obese diabetic patients quickly improves glucose control, independently from weight loss. However, the early effects of a very-low-calorie diet (VLCD) on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes are still unclear. OBJECTIVE The objective was to study the relative contributions of insulin sensitivity, insulin secretion, or both to improvement in glucose metabolism, after 1 wk of caloric restriction, in severely obese diabetic patients. DESIGN Hyperglycemic clamps were performed in 14 severely obese (BMI, in kg/m(2): >40) patients with type 2 diabetes in good glucose control (glycated hemoglobin < 7.5%) before and after 7 d of a VLCD (400 kcal/d). RESULTS The VLCD caused a 3.22 ± 0.56% weight loss (P < 0.001), 42.0% of which was fat loss, accompanied by decreases in fasting plasma glucose (P < 0.05) and triglycerides (P < 0.01). In parallel, the Disposition Index, which measures the bodys capability to dispose of a glucose load, increased from 59.0 ± 6.3 to 75.5 ± 6.3 mL· min(-1) · m(-2) body surface area (P < 0.01), because of improvements in indexes of both first- and second-phase insulin secretion (P < 0.02), but with no changes in insulin sensitivity (P = 0.33). CONCLUSION The marked improvement in metabolic profile, observed in severely obese patients with type 2 diabetes after a 7-d VLCD, was primarily due to the amelioration of β cell function, whereas no contribution of insulin sensitivity was shown. This trial was registered at www.clinicaltrials.gov as NCT01447524.

Cerebral Hemodynamics and Systemic Endothelial Function Are Already Impaired in Well-Controlled Type 2 Diabetic Patients, with Short-Term Disease

Objective Impaired cerebral vasomotor reactivity (VMR) and flow-mediated dilation (FMD) were found in selected subgroups of type 2 diabetes mellitus (T2DM) patients with long-term disease. Our study aimed to evaluate cerebral hemodynamics, systemic endothelial function and sympatho-vagal balance in a selected population of well-controlled T2DM patients with short-term disease and without cardiac autonomic neuropathy (CAN). Research Design and Methods Twenty-six T2DM patients with short-term (4.40±4.80 years) and well-controlled (HbA1C = 6.71±1.29%) disease, without any complications, treated with diet and/or metformin, were consecutively recruited. Eighteen controls, comparable by sex and age, were enrolled also. Results FMD and shear rate FMD were found to be reduced in T2DM subjects with short-term disease (8.5% SD 3.5 and 2.5 SD 1.3, respectively) compared to controls (15.4% SD 4.1 and 3.5 SD 1.4; p<.001 and p<.05). T2DM patients also displayed reduced VMR values than controls (39.4% SD 12.4 vs 51.7%, SD 15.5; p<.05). Sympatho-vagal balance was not different in T2DM patients compared to healthy subjects. FMD and shear rate FMD did not correlate with VMR in T2DM patients or in controls (p>.05). Conclusions In well-controlled T2DM patients with short-term disease cerebral hemodynamics and systemic endothelial function are altered while autonomic balance appeared to be preserved.

Acute hyperglycemia reduces cerebrovascular reactivity: The role of glycemic variability

CONTEXT Cerebral vasomotor reactivity (CVR) is reduced in patients with diabetes mellitus (DM), and glucose variability (GV) might be responsible for cerebrovascular damage. OBJECTIVE Studying patients with insulin resistance without DM, we explored the role of GV in impairing CVR. PATIENTS We studied 18 metabolic syndrome (MS) patients without DM, 9 controls (C), and 26 patients with DM. MAIN OUTCOME MEASURES Groups were compared in terms of CVR, GV, and 24-hour blood pressure. To evaluate the impact of acute hyperglycemia on CVR, a hyperglycemic clamp was performed in MS patients and controls. RESULTS Baseline CVR was reduced in DM vs C and MS (C vs DM = 20.2, 95% CI = 3.5-36.9, P = .014; and MS vs DM = 22.2, 95% CI = 8.6-35.8, P = .001), but similar between MS and C (MS vs C = 2.0, 95% CI = -14.7 to 18.7, P = .643). During acute hyperglycemia, CVR fell in MS and C to values comparable to DM. GV progressively increased from C to MS to DM. In MS, CVR at 120 minutes and GV displayed a negative correlation (r = -0.48, P = .043), which did not change after controlling for mean 24-hour systolic and diastolic blood pressure. In MS, the CVR reduction was significantly correlated to GV (r = 0.55, P = .02). CONCLUSIONS GV is increased in patients with MS but without DM and is the major predictor of CVR reduction induced by acute hyperglycemia, possibly representing the earliest cause of cerebrovascular damage in DM.

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.

The need for identifying standardized indices for measuring glucose variability.

We read the article by Siegelaar and colleagues,1 which clearly suggests the lack of association between glycemic variability (GV) and oxidative stress estimated by 8-iso-prostaglandin F2α (8-iso-PGF2α) excretion rate in patients with type 2 diabetes mellitus (T2DM) with good metabolic control by oral glucose lowering agents. We have, however, some concerns. As an index of GV, mean amplitude of glycemic excursions (MAGE), one of the most widely used indexes for measuring GV, was chosen; although a gold-standard procedure is still lacking. In our article,2 we observed a positive correlation between 8-iso-PGF2α and GV, measured as continuous overall net glycemic action (CONGA-2), in diabetic patients with short-term disease and optimal metabolic control. However, we were unable to show a significant correlation between MAGE and 8-iso-PGF2α. The observation of a different behavior between CONGA-2 and MAGE, in terms of association with oxidative stress, is possibly due to the metabolic characteristics of our patients. In fact, CONGA-2 is known to detect small glycemic swings, occurring over short-time intervals,3 thus appropriately describing the glycemic fluctuations of patients in optimal metabolic balance, without peaks and valleys. On the other side, MAGE displays several limitations, the most important being the arbitrary definition of significant peaks and nadirs in units of standard deviations. Moreover, the raw glycemic data, obtained by continuous glucose monitoring, are usually asymmetric (hypoglycemic is much narrower than hyperglycemic range). Hence, we believe that because MAGE analysis is based on the standard deviation value, as a consequence, we can predict that MAGE will preferentially look at hyperglycemic peaks and will be relatively insensitive to hypoglycemic nadirs.3 Therefore, we suggest applying different indices for the measurement of GV, depending on the aim of the study and the metabolic characteristics of the studied population. We should also consider the possible confounding effect of insulin secretagogues and of the various drugs used in the population studied by Siegelaar and colleagues1 on GV and on oxidative stress parameters.4 In our study, in order to avoid these important confounding factors, we selected patients treated only by either diet alone or diet plus metformin. On the other side, it should be noted that, in agreement with our data, the population studied by Siegelaar and associates1 showed an optimal glycemic control, thus excluding the possible interference of glucotoxicity5 on the results observed. Noteworthy is the utilization of high-performance liquid chromatography tandem mass spectrometry for the quantification of oxidative stress, which is known to represent the reference method for isoprostane measurement.6 In conclusion, the impact of GV on oxidative stress activation in T2DM patients is still under debate. We believe that most of the discrepancies between different findings could be largely overcome by standardizing the use of different GV indices according to clinical characteristics and specific aims. This could help in choosing the most appropriate GV index, measuring the different facets of glucose change over time, in different settings.

Severe hypoglycemia in patients with known diabetes requiring emergency department care: A report from an Italian multicenter study

Highlights • Patients were frail and had a high prevalence of serious comorbidities.• Insulin treatment was the most important cause of severe hypoglycemia.• Among oral drugs, glibenclamide and repaglinide were the main used.• The rate of all-cause mortality was similar with that reported in other studies.• Liver and kidney diseases were the main predictors of hospitalization.

Comment on: Kromhout et al. n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes.

We read the article by Kromhout et al. (1) with interest. The authors clearly suggest that lowdose supplementation of the n-3 fatty acids eicosapentaenoic acid, docosahexaenoic acid, and a-linolenic acid significantly reduces ventricular arrhythmia–related events in postmyocardial infarction patients with diabetes. An abnormal cardiac repolarization, due to an imbalance of the autonomic nervous system, could link diabetes and cardiac arrhythmias, as an association was shown between autonomic neuropathy (AN) and abnormalities in sympathovagal balance and QT interval prolongation (2) in diabetic patients. The sympathovagal balance, expressed as low frequency:high frequency (LF:HF) ratio, represents themost accuratemeasure of sympathovagal balance (2). We have previously shown that acute hyperglycemia increases LF:HF ratio in patients with type 2 diabetes without AN and in healthy control subjects but not in diabetic patients with AN (2). We also demonstrated that glycemic variability is associated with an increased LF:HF ratio in newly diagnosed type 2 diabetic patients with good glycemic control and without AN (3). Hyperglycemia activates the sympathetic nervous system, probably through the activation of the oxidative stress pathway and a reduction of nitric oxide availability (4). The lack of effects of hyperglycemia on the LF:HF ratio in patients with AN is likely related to the fact that, in the presence of AN, nitric oxide is already maximally reduced, following prolonged oxidative stress, and is not further influenced by hyperglycemia. However, although in diabetic patients without AN, hyperglycemia is still able to induce a sympathetic stimulation, we have shown that it failed to increase corrected QT (QTc) interval. This blunted response of QTc to hyperglycemia observed both in patients with and without AN, suggests that the diabetic state per se causes a “dysautonomic state,” possibly through the activation of mechanisms related to chronic hyperglycemia (oxidative stress, endothelial dysfunction) (2). Omega-3 polyunsatured fatty acids (PUFAs) have been shown to increase resting heart rate variability (5), possibly through an enhanced baseline cardiac parasympathetic tone. Therefore, the cardiovascular benefits ascribed to dietary n-3 PUFAs could be due, at least in part, to the improvements in cardiac autonomic balance (5). We demonstrated that a 6-month treatment with PUFA significantly decreases sympathovagal balance during the night and significantly increases the physiological nocturnal fall of QTc, in diabetic patients without AN but not in those with AN (2), probably because of an irreversible damage of the autonomic nervous system. In conclusion, we suggest that the observation made by Kromhout et al. of a reduction in ventricular arrhythmia– related events in diabetic patients treated with a combination of icosapentaenoic acid, docosahexaenoic acid, anda-linolenic acid after a myocardial infarction can be explained by a reduction of sympathetic prevalence during the night and a restoration of normal cardiac conduction. Our observation of a lacking effect of PUFA supplementation in patients with cardiac AN suggests that 1) PUFA may represent a useful treatment in the prevention of abnormalities in cardiac conduction, only before the onset of irreversible damage of the autonomic nervous system; and 2) diabetic AN should be considered when interpreting data from literature.