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

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastro- paresis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brit- tle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal (GI), genitourinary, and cardiovascular). GI distur- bances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal inconti- nence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to con- sideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunc- tion should be performed for individuals with diabetes who have recurrent urinary tract infec- tions, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; mea- surement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve func- tion; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an in- creased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of auto- nomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing) be used for longitudi- nal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing re- quires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recom- mended tests for assessing CAN is readily per- formed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of au- tonomic dysfunction earlier) serves to estab- lish a baseline, with which 1-year interval tests can be compared. Regular HRV testing pro- vides early detection and thereby promotes timely diagnostic and therapeutic interven- tions. HRV testing may also facilitate differen- tial diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and diz- ziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to im- prove metabolic control and to use therapies such as ACE inhibitors and -blockers, proven to be effective for patients with CAN. Diabetes Care 26:1553-1579, 2003

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Diabetic Autonomic Neuropathy

https://www.nutricity.it/wp-content/uploads/2013/02/liee-guida-sul-trattamento-della-gastroparesi.pdf

Clinical Guideline: Management of Gastroparesis

Endothelial dysfunction is a well established response to cardiovascular risk factors and precedes the development of atherosclerosis. Endothelial dysfunction is involved in lesion formation by the promotion of both the early and late mechanisms of atherosclerosis including up-regulation of adhesion molecules, increased chemokine secretion and leukocyte adherence, increased cell permeability, enhanced low-density lipoprotein oxidation, platelet activation, cytokine elaboration, and vascular smooth muscle cell proliferation and migration. Endothelial dysfunction is a term that covers diminished production/availability of nitric oxide and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors. Also, when cardiovascular risk factors are treated the endothelial dysfunction is reversed and it is an independent predictor of cardiac events. We review the literature concerning endothelial dysfunction in regard to its pathogenesis, treatment, and outcome.

Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome.

Thiazolidinediones(TDs)是一类新型的胰岛素抵抗治疗药物。动物及临床实验证实TDs通过激活核受体过氧化物酶体增殖物激活受体-γ(PPAR-γ)显著增加胰岛素敏感性，改善胰岛β-细胞功能，降低血糖和胰岛素水平，缓解高血压及脂代谢紊乱，对2型糖尿病大血管和微血管病变亦具有保护作用。临床使用耐受性好，低血糖发生率低。但其中的Troglitazone具有明显的肝脏毒性。

胰岛素增敏剂一Thiazolidinediones研究现状

Context: Vitamin D receptors are present in many tissues. Hypovitaminosis D is considered to be a risk factor for atherosclerosis. Objective: This study explores the effects of vitamin D replacement on insulin sensitivity, endothelial function, inflammation, oxidative stress, and leptin in vitamin D-deficient subjects. Design, Setting, and Patients: Twenty-three asymptomatic vitamin D-deficient subjects with 25-hydroxyvitamin D [25(OH)D] levels below 25 nmol/liter were compared with a control group that had a mean 25(OH)D level of 75 nmol/liter. The vitamin D-deficient group received 300,000 IU im monthly for 3 months. The following parameters were evaluated before and after treatment: vitamin D metabolites, leptin, endothelial function by brachial artery flow mediated dilatation (FMD), insulin sensitivity index based on oral glucose tolerance test, and lipid peroxidation as measures of thiobarbituric acid reactive substances (TBARS). Results: FMD measurements were significantly lower in 25(OH)D-deficient...

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Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects.

Background: Hyperprolactinemia has been reported to be associated with abnormalities of carbohydrate metabolism. The aim of this study was to evaluate the effects of hyperprolactinemia and bromocriptine (Brc) treatment on endothelial function, insulin sensitivity and inflammatory markers in pre-menopausal women. Methods: Sixteen hyperprolactinemic pre-menopausal women with pituitary adenomas were recruited and 20 healthy subjects were included as controls. Patients were given Brc in doses of 2.5 ‐ 20 mg/dl until normal levels of prolactin were reached. Prior to treatment and 2 months after prolactin levels were normalized, the following tests were performed. Insulin sensitivity was determined by an oral glucose tolerance test based on a formula named the insulin sensitivity index (ISI composite). Endothelial function was measured as flow-mediated dilatation (FMD) on a brachial artery using high resolution ultrasound. Results: Serum glucose, insulin, estrogen, highly sensitive C-reactive protein (hsCRP), fibrinogen, homocysteine and uric acid levels were measured. Calculated ISI composite and FMD were significantly lower in the hyperprolactinemic group in comparison with the controls and improved after Brc treatment. Serum homocysteine, hsCRP and uric acid levels were significantly higher in hyperprolactinemic patients than in the controls and returned to normal levels with Brc treatment. Serum prolactin concentrations were inversely correlated with FMD measurements (r ¼ 2 0.68; P , 0.0001), ISI composite (r ¼ 2 0.48; P , 0.005) and serum estrogen (r ¼ 2 0.54; P , 0.005), and positively correlated with serum homocysteine concentrations (r ¼ 0.55; P , 0.0001) in the hyperprolactinemic group. Conclusions: The hyperprolactinemic state is associated with impaired endothelial function and decreased insulin sensitivity, which are early markers of atherosclerosis. These alterations may predispose to the development of atherosclerosis in non-treated cases. Correction of the hyperprolactinemic state is associated with improved endothelial function and insulin sensitivity.

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Endothelial function, insulin sensitivity and inflammatory markers in hyperprolactinemic pre-menopausal women

OBJECTIVE To compare the effects of erythromycin and metoclopramide on gastric emptying and symptoms of gastroparesis in diabetic patients with delayed gastric emptying.

RESEARCH DESIGN AND METHODS The study group consisted of 13 patients with symptoms of severe gastroparesis and delayed gastric emptying. Gastric emptying was evaluated using a radionuclide method, and gastrointestinal symptoms were scored. The patients were given either erythromycin (250 mg 3 times/day) or metoclopramide (10 mg 3 times/day) in random order for 3 wk, and after a washout period of 3 wk they were crossed-over to the other medication for another 3 wk. Parameters of gastric emptying were assessed before treatment and after both erythromycin and metoclopramide administration.

RESULTS The half-time of gastric emptying in diabetic subjects was 110 (77–120) min before treatment. At 60 and 90 min, the median value of residual isotope activity was 66.5 (55–83.5) and 55% (43–74.3), respectively. The half-time decreased to 55 min (28.6–115) after 3 wk of treatment with erythromycin and percentages of meal retention in the stomach at 60 and 90 min were 49.9 (38.4–70) and 40.5% (29.7–60), respectively. After taking metoclopramide, the median value of half-time was 67 min (15–115) and percentages of meal retention at 60 and 90 min were 51 (34.5–93.9) and 42% (24–71.2), respectively. When compared with baseline values a significant difference in gastric emptying parameters was found after both erythromycin and metoclopramide. A significant improvement of the total score for gastrointestinal symptoms was observed with both drugs, but this improvement was more pronounced with erythromycin.

CONCLUSIONS Erythromycin, a macrolide antibiotic and a motilin receptor agonist, appears to stimulate intestinal motility and seems to be an alternative agent for the treatment of gastroparesis caused by diabetic autonomic neuropathy.

Comparison of Metoclopramide and Erythromycin in the Treatment of Diabetic Gastroparesis

A higher incidence of cardiovascular diseases (CVDs) in winter may be associated with seasonal decrease in vitamin D levels. A recent study reported a clear risk of CVD in vitamin D-deficient patients without prior CVD. The results of several studies suggest that hypovitaminosis D may trigger insulin resistance and endothelial dysfunction, both of which play a role in the development of atherosclerosis. This study investigated the effects of hypovitaminosis D and vitamin D replacement therapy on serum leptin, insulin resistance, endothelial function, and oxidative stress markers in asymptomatic 25-hydroxyvitamin D [25(OH)D]-deficient subjects. The study group subjects were 23 volunteers with 25(OH)D levels below 25 nmol/L. The control group was comprised of 23 age- and sex-matched subjects with normal 25(OH)D levels (mean, 75 nmol/L). The 25(OH)D-deficient group were treated with 300,000 IU of vitamin D3 administered intramuscularly once a month for 3 months. Parameters evaluated before and after treatment included vitamin D metabolites, leptin, lipid peroxidation through measurement of thiobarbituric acid reactive substances (TBARS), insulin sensitivity index based on fasting oral glucose tolerance, and endothelial function evaluated by flow-mediated dilatation (FMD) of the right brachial artery. FMD measurements in the 25(OH)D-deficient group were significantly lower than controls (7.0 ± 3.2 vs. 11.2 ± 5.2%; P = 0.001) and improved after treatment (P = 0.002). A significant reduction occurred in the levels of TBARS after treatment (2.9 ± 0.7 ng/mg MDA; P = 0.0001). FMD was correlated positively with the 25(OH)D level (r = 0.45; P = 0.001) but there was a negative correlation with TBARS (r = -0.28; P < 0.05). Leptin levels increased significantly after treatment (502 ± 240.7 pg/mL; P = 0.001) and the levels positively correlated with the 25(OH)D level (r = 0.50; P = 0.001). These findings demonstrate a relationship between vitamin D levels and endothelial function in asymptomatic vitamin D-deficient individuals and are consistent with previous studies suggesting an association between hypovitaminosis D and atherosclerosis.

Effect of Vitamin D Deficiency and Replacement on Endothelial Function in Asymptomatic Subjects

Magnesium has been shown to increase bone mineral density when used in the treatment of osteoporosis, yet its mechanism of action is obscure. In this study, the effects of daily oral magnesium supplementation on biochemical markers of bone turnover were investigated. Twenty postmenopausal women have been divided into two groups. Ten patients were given magnesium citrate (1,830 mg/day) orally for 30 days. Ten postmenopausal women of matching age, menopause duration, and BMI were recruited as the control group and followed without any medication. Fasting blood and first-void urine samples were collected on days 0, 1, 5, 10, 20, and 30, respectively. Total magnesium, calcium, phosphorus, iPTH and osteocalcin were determined in blood samples. Deoxypyridinoline levels adjusted for creatinine were measured in urine samples. Thirty consecutive days of oral magnesium supplementation caused significantly decrease in serum iPTH levels in the Mg-supplemented group (p < 0.05). Serum osteocalcin levels were significantly increased (p < 0.001) and urinary deoxypyridinoline levels were decreased (p < 0.001) in the Mg-supplemented group. This study has demonstrated that oral magnesium supplementation in postmenopausal osteoporotic women suppresses bone turnover.

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Sema Akalin

Papers

Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects.

Endothelial function, insulin sensitivity and inflammatory markers in hyperprolactinemic pre-menopausal women

Comparison of Metoclopramide and Erythromycin in the Treatment of Diabetic Gastroparesis

Effect of Vitamin D Deficiency and Replacement on Endothelial Function in Asymptomatic Subjects

Short-term oral magnesium supplementation suppresses bone turnover in postmenopausal osteoporotic women.