XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

Parathyroid hormone (PTH) secretion is reg-ulated by a cell surface Ca 2 1 receptor that detects small changesin the level of plasma Ca 2 1 . Because this G protein-coupledreceptor conceivably provides a distinct molecular target fordrugs useful in treating bone and mineral-related disorders, wesought to design small organic molecules that act on the Ca 2 1 receptor. We discovered that certain phenylalkylamine com-pounds, typified by NPS R-568 and its deschloro derivative NPSR-467, increased the concentration of cytoplasmic Ca 2 1 ([Ca 2 1 ] i ) in bovine parathyroid cells and inhibited PTH secre-tion at nanomolar concentrations. These effects were stereose-lective and the R enantiomers were 10- to 100-fold more potentthan the S enantiomers. NPS R-568 potentiated the effects ofextracellular Ca 2 1 on [Ca 2 1 ] i and PTH secretion but waswithout effect in the absence of extracellular Ca 2 1 . Both com-pounds shifted the concentration–response curves for extracel-lular Ca 2 1 to the left. Presumably, these compounds act aspositive allosteric modulators to increase the sensitivity of theCa

Calcimimetics with potent and selective activity on the parathyroid calcium receptor (cytoplasmic Ca21yhyperparathyroidismyparathyroid cellsyNPS R-568yNPS R-467)

The impact of sleep amount and sleep quality on glycemic control in type 2 diabetes: A systematic review and meta-analysis

Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.

The multifaceted role of iron in renal health and disease.

Generating reactive oxygen species (ROS) is necessary for both physiology and pathology. An imbalance between endogenous oxidants and antioxidants causes oxidative stress, contributing to vascular dysfunction. The ROS-induced activation of transcription factors and proinflammatory genes increases inflammation. This phenomenon is of crucial importance in patients with chronic kidney disease (CKD), because atherosclerosis is one of the critical factors of their cardiovascular disease (CVD) and increased mortality. The effect of ROS disrupts the excretory function of each section of the nephron. It prevents the maintenance of intra-systemic homeostasis and leads to the accumulation of metabolic products. Renal regulatory mechanisms, such as tubular glomerular feedback, myogenic reflex in the supplying arteriole, and the renin-angiotensin-aldosterone system, are also affected. It makes it impossible for the kidney to compensate for water-electrolyte and acid-base disturbances, which progress further in the mechanism of positive feedback, leading to a further intensification of oxidative stress. As a result, the progression of CKD is observed, with a spectrum of complications such as malnutrition, calcium phosphate abnormalities, atherosclerosis, and anemia. This review aimed to show the role of oxidative stress and inflammation in renal impairment, with a particular emphasis on its influence on the most common disturbances that accompany CKD.

https://www.mdpi.com/2076-3921/9/8/752/pdf

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease.

Sarcopenia has become a serious disorder in modern society. Chronic kidney disease requiring dialysis and diabetes are some of the disorders that accelerate the onset and progression of sarcopenia. We, therefore, investigated the prevalence of sarcopenia in patients undergoing hemodialysis (HD) and confirmed the impact of diabetes mellitus (DM) on this population. This study included 308 patients whose muscle strength and mass had been evaluated using handgrip strength and dual-energy X-ray absorptiometry, respectively. Sarcopenia was defined according to the criteria established by the Asian Working Group on Sarcopenia. In addition, this cohort had been followed up for 9 years. The prevalence of sarcopenia was 40% (37% in males and 45% in females) with gender differences being insignificant (p = 0.237). The DM morbidity rate was significantly higher in those with sarcopenia than in those without sarcopenia (41% vs. 27%, p = 0.015). Multivariate regression analyses showed that the presence of DM was an independent contributor to sarcopenia in patients undergoing HD (odds ratio 3.11; 95% confidence interval 1.63–5.93; p <  0.001). During the follow-up of 76 ± 35 months, 100 patients died. Patients with sarcopenia demonstrated significantly higher rates of all-cause mortality than those without sarcopenia (p <  0.001 using the log-rank test). Multivariate Cox proportional hazards analyses revealed that the presence of DM was significantly associated with higher all-cause mortality (adjusted hazard ratio: 2.39; 95% confidence interval 1.51–3.81; p <  0.001). The prevalence of sarcopenia among this cohort of patients undergoing HD was determined to be 40%. Moreover, the presence of DM was an independent contributor to sarcopenia and an independent predictor of all-cause mortality in this population.

/pdf/impact-of-diabetes-on-sarcopenia-and-mortality-in-patients-2la47ytssw.pdf

Impact of diabetes on sarcopenia and mortality in patients undergoing hemodialysis

Objective Poor sleep quality is an independent predictor of cardiovascular events. However, little is known about the association between glycemic control and objective sleep architecture and its influence on arteriosclerosis in patients with type-2 diabetes mellitus (DM). The present study examined the association of objective sleep architecture with both glycemic control and arteriosclerosis in type-2 DM patients. Design Cross-sectional study in vascular laboratory. Methods The subjects were 63 type-2 DM inpatients (M/F, 32/31; age, 57.5±13.1) without taking any sleeping promoting drug and chronic kidney disease. We examined objective sleep architecture by single-channel electroencephalography and arteriosclerosis by carotid-artery intima-media thickness (CA-IMT). Results HbA1c was associated significantly in a negative manner with REM sleep latency (interval between sleep-onset and the first REM period) (β=-0.280, p=0.033), but not with other measurements of sleep quality. REM sleep latency associated significantly in a positive manner with log delta power (the marker of deep sleep) during that period (β=0.544, p=0.001). In the model including variables univariately correlated with CA-IMT (REM sleep latency, age, DM duration, systolic blood pressure, and HbA1c) as independent variables, REM sleep latency (β=-0.232, p=0.038), but not HbA1c were significantly associated with CA-IMT. When log delta power was included in place of REM sleep latency, log delta power (β=-0.257, p=0.023) emerged as a significant factor associated with CA-IMT. Conclusions In type-2 DM patients, poor glycemic control was independently associated with poor quality of sleep as represented by decrease of REM sleep latency which might be responsible for increased CA-IMT, a relevant marker for arterial wall thickening.

/pdf/association-between-poor-glycemic-control-impaired-sleep-2syk9sqf7u.pdf

Association between Poor Glycemic Control, Impaired Sleep Quality, and Increased Arterial Thickening in Type 2 Diabetic Patients

Objective: Low thyroid function may be associated with a reduced glomerular filtration rate (GFR) calculated on the basis of creatinine metabolism. Thyroid hormone directly affects serum creatinine in muscle and low thyroid function might exert a similar direct effect in the kidney. The goal of the study was to evaluate this possibility by assessment of the inulin-based GFR and to examine the mechanism underlying the reduction of GFR. Patients and methods: Renal and glomerular hemodynamics were assessed by simultaneous measurements of plasma clearance of para-aminohippurate (CPAH ) and inulin (Cin) in 26 patients with serum creatinine !1.00 mg/dl and without thyroid disease. All subjects were normotensive with or without antihypertensive treatment and were kept in a sodium-replete state. Renal and glomerular hemodynamics were calculated using Gomez’s formulae. Results: Serum TSH, including within the normal range (0.69‐4.30 mIU/ml), was positively correlated with vascular resistance at the afferent arteriole (Ra )( rZ0.609, PZ0.0010), but not at the efferent arteriole (Re). Serum TSH was significantly and negatively correlated with renal plasma flow (RPF), renal blood flow (RBF), and GFR (rZK0.456, PZ0.0192; rZK0.438, PZ0.0252; rZK0.505, PZ0.0086 respectively). In multiple regression analysis, serum TSH was significantly positively associated with Ra after adjustment for age and mean blood pressure. Conclusions: These findings suggest that low thyroid function, even within the normal range, is associated with reduced RPF, RBF, and GFR, which might be caused by a preferential increase in Ra.

/pdf/relationship-between-serum-tsh-levels-and-intrarenal-131amvz68w.pdf

Relationship between serum TSH levels and intrarenal hemodynamic parameters in euthyroid subjects

OBJECTIVE Serum creatinine levels are lower in diabetic patients compared with their nondiabetic counterparts. Therefore, estimated glomerular filtration rate (eGFR) is higher in the former than in the latter group. Factors associated with overestimation of renal function in diabetic patients were examined, and new formulae reflecting precise eGFR were created. RESEARCH DESIGN AND METHODS Eighty subjects (age 56.5 ± 15.4 years; 35 males [43.8%]; 40 patients with diabetes and 40 nondiabetic subjects) were enrolled. GFR was evaluated by inulin clearance (Cin). eGFR values were calculated based on serum creatinine and/or serum cystatin C levels. The factors related to the dissociation between eGFR and Cin in diabetic patients and the agreement among each of three eGFR and Cin were compared. RESULTS Although Cin was not significantly different between the diabetic and nondiabetic subjects (P = 0.2866), each of three eGFR measures from the diabetic patients was significantly higher than that of the nondiabetic subjects (P < 0.01). There were significant and positive correlations between the ratio of each eGFR/Cin, hemoglobin A1c, and glycated albumin. The intraclass correlation coefficients in diabetic patients were weaker than those in the nondiabetic subjects, and the intercepts of the regression lines between each eGFR measure and Cin in the diabetic patients were significantly higher than those of the nondiabetic subjects. New formulae for the calculation of eGFR corrected by the glycemic control indices were better than the original eGFR, particularly in diabetic patients. CONCLUSIONS eGFR overestimates Cin as glycemic controls worsen. eGFR corrected by hemoglobin A1c is considered to be clinically useful and feasible.

https://care.diabetesjournals.org/content/diacare/37/3/596.full.pdf

Poor glycemic control is a major factor in the overestimation of glomerular filtration rate in diabetic patients

Background/Aims: Hyperuricemia has been reported to affect renal hemodynamics in rat models. We evaluate the relationship between serum uric acid and intrarenal hemodynamic parameters in humans, utilizing the plasma clearance of para-aminohippurate (CPAH ) and inulin (Cin). Methods: Renal and glomerular hemodynamics were assessed by simultaneous measurement of CPAH and Cin in 58 subjects. Of these, 19 subjects were planned to provide a kidney for transplantation; 26 had diabetes without proteinuria; and 13 had mild proteinuria. Renal and glomerular hemodynamics were calculated using Gomez`s formulae. Results: Cin was more than 60 ml/min/1.73m2 in all subjects. Serum uric acid levels correlated significantly with vascular resistance at the afferent arteriole (Ra) (r = 0.354, p = 0.006) but not with that of the efferent arteriole (Re). Serum uric acid levels (β = 0.581, p = a after adjustment for several confounders (R2 = 0.518, p = Conclusions: These findings suggest, for the first time in humans, that higher serum uric acid levels are associated significantly with Ra in subjects with Cin > 60 ml/min/1.73m2. The increase in Ra in subjects with higher uric acid levels may be related to dysfunction of glomerular perfusion.

/pdf/relationship-between-serum-uric-acid-levels-and-intrarenal-4dh2wzx1m3.pdf

Akihiro Tsuda

Papers

Impact of diabetes on sarcopenia and mortality in patients undergoing hemodialysis

Association between Poor Glycemic Control, Impaired Sleep Quality, and Increased Arterial Thickening in Type 2 Diabetic Patients

Relationship between serum TSH levels and intrarenal hemodynamic parameters in euthyroid subjects

Poor glycemic control is a major factor in the overestimation of glomerular filtration rate in diabetic patients

Relationship Between Serum Uric Acid Levels and Intrarenal Hemodynamic Parameters