Interfacing Continuous Measurement of Glucose and Physical Activity to Predict Glycemic Control in Individuals with Type 2 Diabetes

Physical activity is a cornerstone in the management of hyperglycemia and risk of cardiovascular disease in type 2 diabetes (T2D). However, the dose response relationship between physical activity and glucose regulation is not well defined. The overall goal of this dissertation was to assess the magnitude and timing of changes of daily glucose concentrations in response to continuous and intermittent light physical activity in T2D. Through utilizing continuous glucose monitors (CGM) and physical activity monitoring concurrently, we were able to assess the glycemic impact of physical activity and sedentary behavior in the free-living environment. Study 1 aimed to examine the effect of regularly interrupting 7-h of prolonged sitting (SIT) with brief bouts of light walking (LW) or simple resistance activities (SRA) on 22-h glucose homeostasis in adults with T2D. Twenty-four individuals with T2D completed 3 conditions (SIT, LW and SRA) in the laboratory. A CGM was worn during the laboratory conditions and in the free-living environment through next morning. Compared to SIT, both LW and SRA reduced mean 22-h glucose concentrations (SIT: 11.5±0.3, LW: 8.7±0.3 and SRA: 8.8±0.3 mmol.L-1), daily duration of hyperglycemia (SIT: 14.7±0.9, LW: 6.3±0.8 and SRA: 6.3±0.9 hours), and mean glucose concentrations through to the next morning. Study 2 compared the effect of increasing physical activity by breaking up sitting time after meals (BR) or by a continuous bout of morning walking (EX) on daily and postprandial glucose (PPG) concentrations (measured by CGM). Thirty individuals with T2D completed EX, BR and a control condition (normal behavior [CON]) in their free-living environment over 1 week. Participants increased their total physical activity in EX and BR by 20, 40 or 60 minutes. Overall, EX was the only condition to significantly lower duration of postprandial glycemia (↓11.4 ± 4.0%) and the 40-minute dose of activity lowered mean PPG. In a subset of participants with high postprandial hyperglycemia at CON (n=9): (1) both EX and BR significantly shortened duration of hyperglycemia and (2) the 40 and 60-minute doses of activity significantly lowered mean PPG. Study 3 evaluated the sex differences in the glucose response to the EX and BR conditions described in Study 2. We found that men had a significant glucose lowering effect of EX and BR compared to control, whereas women’s level of glycemia was unchanged with the activity conditions. This sex difference was driven by higher levels of hyperglycemia in men during the CON condition. This dissertation utilized CGM and physical activity monitors to identify effective interventions to manage hyperglycemia in T2D. The combination of studies performed in the laboratory and free-living environment in this dissertation have potential to better inform physical activity guidelines for the management of T2D

Admission hyperglycemia in patients with acute coronary syndrome complicated by cardiogenic shock

Background: Many reports shoed that for patients with acute coronary syndrome (ACS) increased admission blood glucose (ABG) level is associated with adverse outcomes. Although scientific reports on this issue are still inconsistent, many recent studies confirm that hyperglycemia is also an unfavorable prognostic factor in patients with ACS complicated by cardio­genic shock (CS). The aim of this study is to determine if hyperglycemia on admission can be a predictor of in-hospital death in patients with ACS complicated by CS. Methods: The study population consisted of 40 patients with ACS complicated by CS admit­ted to the Intensive Cardiac Therapy Clinic from January 2010 to May 2013 and treated with primary percutaneous coronary intervention. A control group was selected among patients with uncomplicated ACS. Results: Patients with CS had significantly higher levels of ABG (15.4 ± 6.26 vs. 7.97 ± ± 2.28 mmol/L, p < 0.01) in comparison with the control group. There was no statistically significant correlation between the level of glucose on admission and in-hospital mortality. Average ABG in patients who survived and in those who died were respectively 15.42 ± 5.61 vs. 15.40 ± 6.87 mmol/L, p > 0.05. Comparison in groups depending on ABG level and cal­culations with use of receiver-operating characteristics curves showed no relationship between the level of ABG and patients’ deaths. Conclusions: Hyperglycemia on admission is a clinical feature of patients with ACS who develop CS, however its prognostic value requires further studies

Does autonomic function link social position to coronary risk? The Whitehall II study.

BACKGROUND: Laboratory and clinical studies suggest that the autonomic nervous system responds to chronic behavioral and psychosocial stressors with adverse metabolic consequences and that this may explain the relation between low social position and high coronary risk. We sought to test this hypothesis in a healthy occupational cohort. METHODS AND RESULTS: This study comprised 2197 male civil servants 45 to 68 years of age in the Whitehall II study who were undergoing standardized assessments of social position (employment grade) and the psychosocial, behavioral, and metabolic risk factors for coronary disease previously found to be associated with low social position. Five-minute recordings of heart rate variability (HRV) were used to assess cardiac parasympathetic function (SD of N-N intervals and high-frequency power [0.15 to 0.40 Hz]) and the influence of sympathetic and parasympathetic function (low-frequency power [0.04 to 0.15 Hz]). Low employment grade was associated with low HRV (age-adjusted trend for each modality, P< or =0.02). Adverse behavioral factors (smoking, exercise, alcohol, and diet) and psychosocial factors (job control) showed age-adjusted associations with low HRV (P<0.03). The age-adjusted mean low-frequency power was 319 ms2 among those participants in the bottom tertile of job control compared with 379 ms2 in the other participants (P=0.004). HRV showed strong (P<0.001) linear associations with components of the metabolic syndrome (waist circumference, systolic blood pressure, HDL cholesterol, triglycerides, and fasting and 2-hour postload glucose). The social gradient in prevalence of metabolic syndrome was explained statistically by adjustment for low-frequency power, behavioral factors, and job control. CONCLUSIONS: Chronically impaired autonomic function may link social position to different components of coronary risk in the general population

Evaluation of Glycated Albumin (GA) and GA/Hba1c Ratio for Diagnosis of Diabetes and Glycemic Control: A Comprehensive Review

Diabetes Mellitus (DM) is a group of metabolic diseases characterized by chronic high blood glucose concentrations (hyperglycemia). When it is left untreated or improperly managed, it can lead to acute complications including diabetic ketoacidosis and non-ketotic hyperosmolar coma. In addition, possible long-term complications include impotence, nerve damage, stroke, chronic kidney failure, cardiovascular disease, foot ulcers, and retinopathy. Historically, universal methods to measure glycemic control for the diagnosis of diabetes included fasting plasma glucose level (FPG), 2-h plasma glucose (2HP), and random plasma glucose. However, these measurements did not provide information about glycemic control over a long period of time. To address this problem, there has been a switch in the past decade to diagnosing diabetes and its severity through measurement of blood glycated proteins such as Hemoglobin A1c (HbA1c) and glycated albumin (GA). Diagnosis and evaluation of diabetes using glycated proteins has many advantages including high accuracy of glycemic control over a period of time. Currently, common laboratory methods used to measure glycated proteins are high-performance liquid chromatography (HPLC), immunoassay, and electrophoresis. HbA1c is one of the most important diagnostic factors for diabetes. However, some reports indicate that HbA1c is not a suitable marker to determine glycemic control in all diabetic patients. GA, which is not influenced by changes in the lifespan of erythrocytes, is thought to be a good alternative indicator of glycemic control in diabetic patients. Here, we review the literature that has investigated the suitability of HbA1c, GA and GA:HbA1c as indicators of long-term glycemic control and demonstrate the importance of selecting the appropriate glycated protein based on the patient’s health status in order to provide useful and modern point-of-care monitoring and treatment

Ventricular Arrhythmias Complicating Coronary Artery Disease: Recent Trends, Risk Associated with Serum Glucose Levels, and Psychological Impact

Introduction: Ventricular arrhythmias (VAs) are common after an acute coronary syndrome (ACS) and are associated with worse clinical outcomes. However, little is known about recent trends in their occurrence, their association with serum glucose levels, and their psychological impact in ACS setting. Methods: We examined 25-year (1986-2011) trends in the incidence rates (IRs) and hospital case-fatality rates (CFRs) of VAs, and the association between serum glucose levels and VAs in patients with an acute myocardial infarction (AMI) in the Worcester Heart Attack Study. Lastly, we examined the relationship between in-hospital occurrence of VAs and 12-month progression of depression and anxiety among hospital survivors of an ACS in the longitudinal TRACE-CORE study. Results: We found the IRs declined for several major VAs between 1986 and 2011while the hospital CFRs declined in both patients with and without VAs over this period. Elevated serum glucose levels at hospital admission were associated with a higher risk of developing in-hospital VAs. Occurrence of VAs, however, was not associated with worsening progression of symptoms of depression and/or anxiety over a 12-month follow-up period in patients discharged after an ACS. Conclusions: The burden and impact of VAs in patients with an AMI has declined over time. Elevated serum glucose levels at hospital admission may serve as a predictor for in-hospital occurrence of serious cardiac arrhythmias. In-hospital occurrence of VAs may not be associated with worsening progression of symptoms of depression and anxiety in patients with an ACS

Resistance exercise timing and metabolic risk factors in type 2 diabetics

"July 2014."Dissertation Advisor: Dr. Jill A. Kanaley.Includes vita.Abnormally elevated postprandial glucose and triacylglycerol (TAG) concentrations are risk factors for cardiovascular disease in patients with type-2 diabetes. The most effective time to exercise to lower postprandial glucose and TAG concentrations is unknown. Thus, the aim of this study was to determine what time is more effective, either pre- or post-dinner resistance exercise (RE), at improving postprandial risk factors in patients with type-2 diabetes. Methods: Thirteen obese patients with type 2 diabetes completed three trials in a random order in which they consumed a standardized dinner meal with 1) no RE (NoRE), 2) pre-dinner RE (RE?��M), and 3) post-dinner RE beginning 45 min after dinner (M?��RE). During each trial blood samples were taken to measure glucose, TAG, acetaminophen (gastric emptying), endocrine responses, and mathematical modeling was used to assess beta-cell function. Indirect calorimetry was used to measure energy expenditure and substrate oxidation. A continuous glucose monitor was used to assess nocturnal and morning glycemic control the next day. A fasting blood sample was taken the following morning and the quantitative insulin sensitivity check index (QUICKI) was used to estimate whole body insulin sensitivity and the homeostatic model assessment of insulin resistance (HOMA-IR) was used as an estimate of hepatic insulin resistance. Results: The postprandial glucose iAUC was reduced (P < 0.05) by ?�18% and 30% during the RE?��M and M?��RE trials, respectfully, compared to NoRE, with no difference between RE trials. The postprandial total TAG iAUC was ?�92% lower (P < 0.05) during M?��RE compared to NoRE and RE?��M, an effect due to lower VLDL-1 TAG concentrations. RE?��M and M?��RE reduced the insulin iAUC by 35% and 48%, respectfully, compared to NoRE (P < 0.05), but via different mechanisms as RE?��M enhanced insulin clearance, whereas M?��RE reduced pancreatic insulin secretion and enhanced insulin clearance. The postprandial GLP-1Includes bibliographical references (pages 84-95)

Type 1 Diabetes Mellitus and Premature Coronary Artery Disease

Cardiovascular disease, which affects more than half of all diabetics, is the leading cause of morbidity and mortality in patients with type 1 and type 2 Diabetes Mellitus (DM). Around 55% of diabetes patients are thought to have it, in comparison to 2-4% of the general population. A significant risk factor for the development of Coronary Artery Disease (CAD) exists in people with Type 1 Diabetes Mellitus (T1DM). However, it is worth noting that the present Models of risk prediction for T1DM have a variety of flaws. CAD risk is expected to double or quadruple over the next two to four decades, and diabetes mellitus is the third most significant risk factor for the etiology of illness. As a result, diabetes increases the chance of developing Acute Coronary Syndromes (ACS), whose incidence surpasses 20% after seven years, compared to a rate of 3.5 percent in non-diabetics – a rate comparable to individuals who have already experienced an Acute Myocardial Infarction (AMI). Additionally, it is crucial to identify any well-defined specific risk factors for T1DM as well as any extra subclinical atherosclerosis that may influence these patients at an advanced stage of disease progression. T1DM patients have more severe lesions, a lower left ventricle (LV) ejection fraction, a higher risk of cardiac events, and a higher rate of silent ischemia when compared to non-diabetics. They continue to have impaired microcirculation and endothelial function, both of which contribute to tissue perfusion problems

Alternative Therapy and Treatment of Type 2 Diabetes

The rise in prevalence and incidence of type 2 diabetes mellitus (T2D) in the developing world continues unabated. Current treatment strategies, however, fall short of achieving optimal glycemic control. The aim of project I was to investigate the effect of an acute bout of a yogic breathing exercise on heart rate variability (HRV) in individuals with T2D. Project II was designed to assess the effectiveness of the neurohormone melatonin in lowering short- and long-term glucose levels, lipids and oxidative stress in T2D. Project III investigated the differential effects of two different styles of aerobic exercise on postprandial glycemia, mood and HRV in T2D. Project I investigated the effect of short-term breathing exercises and demonstrated significant differences between the T2D group and an age-matched normoglycemic group (CON) in resting measures of HRV. Standard deviation of consecutive heart beats (SDNN), the square root of the mean squared differences (RMSSD) and total spectral power (TP) were almost uniformly lower in the T2D group than the CON group. A within-group analysis revealed no significant effect of breathing exercise upon HRV in the CON group. However, a 10-minute breathing protocol involving selective breathing through only the left nostril demonstrated a significant reduction in resting heart rate in the T2D group (-1.2 beats per minute, or bpm) compared to the heart rate average during the entire breathing protocol, indicating a possible acute improvement in vagal tone. Project II, which investigated the effect of six weeks of melatonin supplementation on short-and long-term glycemic control, lipids, and oxidative stress in T2D, yielded impressive results. There was a significant reduction in malondialdehyde, a marker of oxidative stress (-6.3 vs. 0.7nmol/ml), as well as a significant drop in glycated hemoglobin (-0.24%±0.23) in the melatonin group vs. the placebo group. Project III examined the impact of a more recreational style of exercise (table tennis) following a dinner meal vs. a more traditional exercise (walking). Our results indicated that self-paced walking generated a significantly higher heart rate than table tennis, which translated into a significant drop in blood glucose levels following a 30-minute bout of exercise. We did not, however, note any difference in mood between the two groups

Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies

Diabetic cardiomyopathy (DCM), although a distinct clinical entity, is also a part of the diabetic atherosclerosis process. It may be independent of the coexistence of ischemic heart disease, hypertension, or other macrovascular complications. Its pathological substrate is characterized by the presence of myocardial damage, reactive hypertrophy, and intermediary fibrosis, structural and functional changes of the small coronary vessels, disturbance of the management of the metabolic cardiovascular load, and cardiac autonomic neuropathy. These alterations make the diabetic heart susceptible to ischemia and less able to recover from an ischemic attack. Arterial hypertension frequently coexists with and exacerbates cardiac functioning, leading to the premature appearance of heart failure. Classical and newer echocardiographic methods are available for early diagnosis. Currently, there is no specific treatment for DCM; targeting its pathophysiological substrate by effective risk management protects the myocardium from further damage and has a recognized primary role in its prevention. Its pathophysiological substrate is also the objective for the new therapies and alternative remedies

α‑Glucosidase inhibitor miglitol attenuates glucose fluctuation, heart rate variability and sympathetic activity in patients with type 2 diabetes and acute coronary syndrome : a multicenter randomized controlled (MACS) study

Background: Little is known about clinical associations between glucose fluctuations including hypoglycemia, heart rate variability (HRV), and the activity of the sympathetic nervous system (SNS) in patients with acute phase of acute coronary syndrome (ACS). This pilot study aimed to evaluate the short-term effects of glucose fluctuations on HRV and SNS activity in type 2 diabetes mellitus (T2DM) patients with recent ACS. We also examined the effect of suppressing glucose fluctuations with miglitol on these variables. Methods: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group comparative study included 39 T2DM patients with recent ACS, who were randomly assigned to either a miglitol group (n = 19) or a control group (n = 20). After initial 24-h Holter electrocardiogram (ECG) (Day 1), miglitol was commenced and another 24-h Holter ECG (Day 2) was recorded. In addition, continuous glucose monitoring (CGM) was performed throughout the Holter ECG. Results: Although frequent episodes of subclinical hypoglycemia (≤4.44 mmo/L) during CGM were observed on Day 1 in the both groups (35% of patients in the control group and 31% in the miglitol group), glucose fluctuations were decreased and the minimum glucose level was increased with substantial reduction in the episodes of subclinical hypoglycemia to 7.7% in the miglitol group on Day 2. Holter ECG showed that the mean and maximum heart rate and mean LF/HF were increased on Day 2 in the control group, and these increases were attenuated by miglitol. When divided 24-h time periods into day-time (0700–1800 h), night-time (1800–0000 h), and bed-time (0000–0700 h), we found increased SNS activity during day-time, increased maximum heart rate during night-time, and glucose fluctuations during bed-time, which were attenuated by miglitol treatment. Conclusions: In T2DM patients with recent ACS, glucose fluctuations with subclinical hypoglycemia were associated with alterations of HRV and SNS activity, which were mitigated by miglitol, suggesting that these pathological relationships may be a residual therapeutic target in such patients