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Biomedical subjects

A I Vinik

Publications and source records attributed to A I Vinik.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of gastroparesis: a multidisciplinary clinical review.

This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Consensus Statements as Topic↗
PubMed2006

Effect of early addition of rosiglitazone to sulphonylurea therapy in older type 2 diabetes patients (>60 years): the Rosiglitazone Early vs. SULphonylurea Titration (RESULT) study.

AIM: To compare the efficacy, safety and tolerability of adding rosiglitazone (RSG) vs. sulphonylurea (SU) dose escalation in older type 2 diabetes mellitus (T2DM) patients inadequately controlled on SU therapy. METHODS: A total of 227 T2DM patients from 48 centres in the USA and Canada, aged > or =60 years, were randomized to receive RSG (4 mg) or placebo once daily in combination with glipizide 10 mg twice daily for 2 years in a double-blind, parallel-group study. Previous SU monotherapy was (1/4) to (1/2) maximum recommended dose for > or =2 months prior to screening with fasting plasma glucose (FPG) > or =7.0 and < or =13.9 mmol/l. Treatment options were individualized, and escalation of study medication was specifically defined. RESULTS: Disease progression (time to reach confirmed FPG > or =10 mmol/l while on maximum doses of both glipizide and study medication or placebo) was reported in 28.7% of patients uptitrating SU plus placebo compared with only 2.0% taking RSG and SU combination (p < 0.0001). RSG + SU significantly decreased HbA(1c), FPG, insulin resistance, plasma free fatty acids and medical care utilization and improved treatment satisfaction compared with uptitrated SU. CONCLUSIONS: Addition of RSG to SU in older T2DM patients significantly improved glycaemic control and reduced disease progression compared with uptitrated SU alone but without increasing hypoglycaemia. These benefits were associated with increased patient treatment satisfaction and reduced medical care utilization with regards to emergency room visits and length of hospitalization. Early addition of RSG is an effective treatment option for older T2DM patients inadequately controlled on submaximal SU monotherapy.

Age Factors↗
PubMed2004

Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects.

BACKGROUND: Using identical methods, three simultaneous placebo-controlled trials of topiramate for painful diabetic neuropathy (PDN) did not reach significance. This independent yet concurrent placebo-controlled trial used different methods to assess topiramate efficacy and tolerability in PDN. METHODS: This 12-week, multicenter, randomized, double-blind trial included 323 subjects with PDN and pain visual analog (PVA) score of at least 40 on a scale from 0 (no pain) to 100 (worst possible pain). Topiramate (n = 214) or placebo (n = 109) was titrated to 400 mg daily or maximum tolerated dose. Short-acting rescue analgesics were permitted only during the first 6 weeks. RESULTS: Baseline characteristics were comparable between groups except for mean body weight (topiramate, 101.4 kg; placebo, 95.7 kg; p = 0.028). Twelve weeks of topiramate treatment reduced PVA scale score (from 68.0 to 46.2 mm) more effectively than placebo (from 69.1 to 54.0 mm; p = 0.038). Fifty percent of topiramate-treated subjects and 34% of placebo-treated subjects responded to treatment, defined as >30% reduction in PVA scale score (p = 0.004). Topiramate monotherapy also reduced worst pain intensity (p = 0.003 vs placebo) and sleep disruption (p = 0.020 vs placebo). Diarrhea, loss of appetite, and somnolence were the most commonly reported adverse events in the topiramate group. Topiramate reduced body weight (-2.6 vs +0.2 kg for placebo; p < 0.001) without disrupting glycemic control. CONCLUSIONS: Topiramate monotherapy reduced pain and body weight more effectively than placebo in patients with painful diabetic neuropathy.

Adolescent↗
PubMed2004

Diabetic neuropathies.

Diabetic neuropathy (DN) is a common complication of diabetes that often is associated with considerable morbidity and mortality. The epidemiology and natural history of DN is clouded with uncertainty because of confusion regarding the definition and measurement of this disorder. The recent resurgence of interest in the vascular hypothesis, oxidative stress, the neurotrophic hypothesis,and the possibility of the role of autoimmunity has opened up new avenues of investigation for therapeutic intervention. The ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on success in uncovering the pathogenic processes underlying this disorder.

Aldehyde Reductase↗
PubMed2001

Small fiber neuropathy and neurovascular disturbances in diabetes mellitus.

Functional and organic abnormalities in small unmyelinated C fibers are the hallmark of type 2 diabetes. These may be silent clinically or present with burning feet, neurovascular abnormalities, wherein warm, cold, and heat pain thresholds are disturbed in association with impairment in skin blood flow and loss of PGP 9.5 immunostaining nerves in the skin. There is a dysfunctional phase preceding organic structural damage to the neurovascular unit. It coexists with elements of the metabolic syndrome, particularly insulin resistance (IR), elevated systolic blood pressure, and diabetic dyslipidemia i.e. dysfunction of the neurovascular unit may contribute to IR due to compromised blood flow with decreased delivery of fuels to their target tissues. If this proves to be the case, it will become important to re-focus energies on the defective neuropeptidergic regulation of blood flow as an approach to ameliorating diabetes. Because there is a functional phase that precedes structural damage, reversibility of the defect is achievable.

Animals↗
PubMed2001

Methods for evaluation of peripheral neurovascular dysfunction.

Measurement of skin blood flow is a sensitive marker of C-fiber neurovascular dysfunction. It precedes development of abnormalities in diabetes mellitus, correlates with in vivo indices of the metabolic syndrome, and may be a "benchmark" for future studies on agents to improve microvascular dysfunction in diabetes mellitus. Skin blood flow can be measured under basal and stimulated conditions. There are different methods of evaluation. Iontophoresis and microdialysis are novel methods of drug delivery and the latter may be used as a means of extracting analytes in the skin. Theses methods are not invasive (iontophoresis) or minimally invasive (microdialysis). They can be performed repeatedly and safely in most patients. The use of microdialysis may be limited by sampling only water-soluble molecules. An alternative to microdialysis is iontophoresis, which works better with polar molecules. A combination of microdialysis and iontophoresis techniques can be useful in assessment of the pharmacokinetics of polar and nonpolar agents and the physiology and pathophysiology of the skin neurovascular system.

Diabetic Angiopathies↗
PubMed2001

Age 85+ years accelerates large-fiber peripheral nerve dysfunction and diabetes contributes even in the oldest-old: the Women's Health and Aging Study.

BACKGROUND: Both diabetes mellitus and advancing age are associated with peripheral nerve dysfunction (PND). However, the independent and potentially synergistic effects of these factors in old age are poorly described, especially among the oldest-old and among people with an existing disability. METHODS: A total of 894 women aged 65+ years participating in the Women's Health and Aging Study received a baseline home interview and clinical examination during which PND was evaluated by the Vibratron II. Age and diabetes were examined in relation to the level of PND (normal, mild, moderate, or severe). Height, alcohol consumption, smoking, report of neurologic symptoms, and diabetes duration were examined as potential confounders. RESULTS: Eighteen percent of the sample reported diabetes, 42% had normal nerve function, and 23.9%, 14.5%, and 19.5% had mild, moderate, and severe PND, respectively. Women aged 85+ years had 6.5, 7.5, and 13.3 times the odds of mild, moderate, and severe PND relative to women aged 65-74 years, adjusted for diabetes and height. Women who reported diabetes had 1.8, 2.4, and 1.6 times the risk of mild, moderate, and severe PND relative to those who did not, adjusted for age and height. No interaction between age and diabetes was observed. CONCLUSIONS: Age is strongly associated with decrements in large-fiber peripheral nerve function in disabled women aged 65+ years, with greatly accelerated risk among those aged 85+ years. Despite the overwhelmingly strong effects of advancing age on PND in this cohort, diabetes remains a significant correlate of PND. Future studies may determine whether prevention or control of diabetes is effective in reducing the occurrence of PND in old age and whether a reduction in PND will translate into reduced disability in this age group.

Age Factors↗
PubMed2001

Dermal neurovascular dysfunction in type 2 diabetes.

OBJECTIVE: To review evidence for a relationship between dermal neurovascular dysfunction and other components of the metabolic syndrome of type 2 diabetes. RESEARCH DESIGN AND METHODS: We review and present data supporting concepts relating dermal neurovascular function to prediabetes and the metabolic syndrome. Skin blood flow can be easily measured by laser Doppler techniques. RESULTS: Heat and gravity have been shown to have specific neural, nitrergic, and independent mediators to regulate skin blood flow. We describe data showing that this new tool identifies dermal neurovascular dysfunction in the majority of type 2 diabetic patients. The defect in skin vasodilation is detectable before the development of diabetes and is partially correctable with insulin sensitizers. This defect is associated with C-fiber dysfunction (i.e., the dermal neurovascular unit) and coexists with variables of the insulin resistance syndrome. The defect most likely results from an imbalance among the endogenous vasodilator compound nitric oxide, the vasodilator neuropeptides substance P and calcitonin gene-related peptide, and the vasoconstrictors angiotensin II and endothelin. Hypertension per se increases skin vasodilation and does not impair the responses to gravity, which is opposite to that of diabetes, suggesting that the effects of diabetes override and counteract those of hypertension. CONCLUSIONS: These observations suggest that dermal neurovascular function is largely regulated by peripheral C-fiber neurons and that dysregulation may be a component of the metabolic syndrome associated with type 2 diabetes.

Diabetes Mellitus, Type 2↗
PubMed2001

Platelet dysfunction in type 2 diabetes.

Insulin resistance is a uniform finding in type 2 diabetes, as are abnormalities in the microvascular and macrovascular circulations. These complications are associated with dysfunction of platelets and the neurovascular unit. Platelets are essential for hemostasis, and knowledge of their function is basic to understanding the pathophysiology of vascular disease in diabetes. Intact healthy vascular endothelium is central to the normal functioning of smooth muscle contractility as well as its normal interaction with platelets. What is not clear is the role of hyperglycemia in the functional and organic microvascular deficiencies and platelet hyperactivity in individuals with diabetes. The entire coagulation cascade is dysfunctional in diabetes. Increased levels of fibrinogen and plasminogen activator inhibitor 1 favor both thrombosis and defective dissolution of clots once formed. Platelets in type 2 diabetic individuals adhere to vascular endothelium and aggregate more readily than those in healthy people. Loss of sensitivity to the normal restraints exercised by prostacyclin (PGI(2)) and nitric oxide (NO) generated by the vascular endothelium presents as the major defect in platelet function. Insulin is a natural antagonist of platelet hyperactivity. It sensitizes the platelet to PGI(2) and enhances endothelial generation of PGI(2) and NO. Thus, the defects in insulin action in diabetes create a milieu of disordered platelet activity conducive to macrovascular and microvascular events.

Animals↗
PubMed2001

Recognizing and treating diabetic autonomic neuropathy.

Diabetic autonomic neuropathy can cause heart disease, gastrointestinal symptoms, genitourinary disorders, and metabolic disease. Strict glycemic control can slow the onset of diabetic autonomic neuropathy and sometimes reverse it. Pharmacologic and nonpharmacologic therapies are available to treat symptoms.

Autonomic Nervous System Diseases↗
PubMed2000

Evidence-based therapy for type 2 diabetes. The best and worst of times.

Type 2 diabetes, which is increasing in prevalence, is a multifaceted disease that presents a challenge to the primary care physician. In this article, Drs Flemmer and Vinik review the significant findings of several important clinical trials and present a method of comprehensive staged management to improve the quality of patient care.

Aged↗
PubMed2000

Neurotrophic role of interleukin-6 and soluble interleukin-6 receptors in N1E-115 neuroblastoma cells.

Interleukin 6 (IL-6) plays a role in physiological and pathophysiological processes in neuronal cells. We studied whether IL-6 plays a role in neuroblastoma cells in culture. These studies demonstrate that N1E-115 cells constitutively express IL-6 but not IL-6R. Exogenous IL-6 stimulated neuronal proliferation in a dose-dependent manner. Under serum-free conditions soluble IL-6 receptors (sIL-6R) alone or in combination with IL-6 exerted significant proliferative effects, while IL-6 alone failed to promote cell proliferation. Neutralizing anti-IL-6 antibody caused a 30-40% reduction in IL-6 mediated proliferation. Our results suggest the importance of IL-6/sIL-6R for proliferation and survival of N1E-115 adrenergic neuroblastoma cells.

Animals↗
PubMed2000

Diabetic neuropathies.

Diabetic neuropathy is a common complication of diabetes that is often associated both with considerable morbidity and mortality. The epidemiology and natural course of diabetic neuropathy is clouded with uncertainty, largely due to confusion regarding the definition and measurement of this disorder. The recent resurgence of interest in the vascular hypothesis, oxidative stress, the neurotrophic hypothesis and the possibility of the role of autoimmunity have opened up new avenues of investigation for therapeutic intervention. Paralleling our increased understanding of the pathogenesis of diabetic neuropathy, there must be refinements in our ability to measure quantitatively the different types of defects that occur in this disorder, so that appropriate therapies can be targeted to specific fibre types. These tests must be validated and standardised to allow comparability between studies and a more meaningful interpretation of study results. Our ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on our success in uncovering the pathogenic processes underlying this disorder.

Aldehyde Reductase↗
PubMed2000

Independent effects of peripheral nerve dysfunction on lower-extremity physical function in old age: the Women's Health and Aging Study.

OBJECTIVE: To determine the role of peripheral nerve dysfunction (PND) in the disablement pathway. RESEARCH DESIGN AND METHODS: Vibration perception threshold (VPT) was measured in 894 women aged > or = 65 years, and those with normal peripheral nerve function and with mild, moderate, and severe PND were identified. Lower-extremity impairments included quadriceps strength (kilograms) and three progressively difficult balance tasks (able/unable). Functional limitations included rising from a chair (able/unable) and usual pace and fast-paced walking speeds (meters/second). Level of PND was related to impairments and functional limitations in linear and logistic regression models that controlled for potentially confounding factors, including reported diabetes. RESULTS: Level of PND was associated with impaired balance (adjusted odds ratios: 2.21, 1.95, and 3.02 for mild, moderate, and severe PND, respectively, relative to normal, P < 0.05). PND was also associated with decrements in both usual and fast-paced walking speeds (-0.08, -0.08, and -0.15 m/s for usual pace and -0.13, -0.12, and -0.24 m/s for fast-paced walking speed for women with mild, moderate, and severe PND, respectively; P < 0.01 for all). Reported diabetes was not associated with these outcomes in the presence of PND. Some, but not all, of the association between PND and functional limitations was explained by the relationship between PND and impairments. CONCLUSIONS: PND is significantly associated with both lower-extremity impairments and functional limitations in older women, and PND appears to have independent effects on functional limitations. The independent effect of diabetes on these outcomes may be limited when PND is considered. Further research is needed to determine if PND is causally related to disability in old age.

Aged↗
PubMed1999

Diabetic neuropathy: pathogenesis and therapy.

Diabetic neuropathies are complex, heterogeneous disorders that encompass a wide range of abnormalities affecting both peripheral and autonomic nervous systems, causing considerable morbidity and mortality. Treatment should be based upon the underlying etiology and not symptoms alone, although symptomatic therapy is needed. Neuropathies may be focal or diffuse, proximal or distal, and involve somatic and autonomic nerves. Focal syndromes are classified as (1) entrapment syndromes or (2) mononeuropathies. Entrapment syndromes are treated by means of relieving compression within confined spaces. Mononeuropathies are due to a vascular insult and resolve spontaneously. They are best treated by supportive therapy. Proximal neuropathies are usually due to an inflammatory, vasculitic, or autoimmune condition and are best treated with specific therapies for the underlying disorder based on biopsy findings. Therapies for distal polyneuropathies include metabolic treatments (e.g., aldose reductase inhibitors, aminoguanidine, gamma-linolenic acid), autoimmune therapies, and nerve growth factors. No definitive treatment is available for painful diabetic neuropathy. Several medications have been used, among them tricyclic antidepressants, antiepileptic drugs, phenothiazines, calcitonin, local anesthetics, nonsteroidal anti-inflammatory drugs, and dextromethorphan. Nonpharmacologic therapies include surgical sympathectomy, spinal cord blockade, electrical spinal cord stimulation, and prostaglandin.

Aldehyde Reductase↗
PubMed1999

Specific fiber deficits in sensorimotor diabetic polyneuropathy correspond to cytotoxicity against neuroblastoma cells of sera from patients with diabetes.

OBJECTIVE: Neuropathy is the most common complication of diabetes, and toxic serum factors may contribute to its genesis. RESEARCH DESIGN AND METHODS: We assessed neurotoxicity in the serum of 39 diabetic patients and correlated it with clinical measures of somatic and autonomic nerve fiber damage. Sera were applied to N1E-115 and VSC4.1 neuroblastoma cells in vitro as models of sensory/autonomic (S/A) and motor neurons, respectively. Neurotoxicity was measured as either complete or near-complete cell death (highly toxic), inhibited cell growth (moderately toxic), or normal cell proliferation (nontoxic) compared with pooled human serum controls during culture over 4 days. RESULTS: There was an inverse correlation between neurotoxicity and vibration perception threshold (P < 0.01). Age (P < 0.02), duration of diabetes (P < 0.02), and HbA1c (P < 0.03) correlated with neurotoxicity, suggesting that glycation may contribute to cytotoxicity in this model. S/A neurotoxicity occurred more frequently in the sera of patients with type 1 (19 of 25) than type 2 (5 of 14) diabetes (P < 0.02). None of the sera from either type 1 or type 2 diabetic patients displayed neurotoxicity on VSC4.1 cells, whereas sera from patients with motor neuropathy were highly toxic. CONCLUSIONS: These studies indicate that there is a relationship between the specific nerve fiber dysfunction in the patient and the type of neuronal cell killed, not only for diabetic neuropathy but also for known forms of autoimmune neuropathies. Such toxic factors may contribute to diabetic neuropathy by acting in concert with hyperglycemia to damage sensory/autonomic neurons.

Analysis of Variance↗
PubMed1999

Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes: a new model for the pathogenesis of microvascular dysfunction.

OBJECTIVE: To test the independent contributions of vascular endothelium, sympathetic activation and inhibition, vessel distensibility, and nociceptor-mediated vasodilation in both glabrous and hairy skin circulations. RESEARCH DESIGN AND METHODS: We measured blood flow using laser Doppler techniques in 10 people with type 2 diabetes and 10 age- and BMI-matched healthy control subjects at the pulp of the index finger (glabrous skin) and the dorsum of the hand (hairy skin). A 5-min ischemic block of the arm was used to test vascular endothelium. Warming of the probe site to 45 degrees C tested neurogenic vasodilation in hairy skin only. Vessel distensibility was tested by gravitational pressure. RESULTS: Basal blood flow and reactive hyperemia did not differ between groups at either skin site. The vasodilative response to local warming (P < 0.01) and limb lowering (P < 0.05) were significantly different between groups in hairy skin but not in glabrous skin in the absence of objective measured neuropathy. Nociceptor-mediated flow correlated significantly with the warm thermal threshold (r = -0.50, P < 0.05). Endothelial-mediated blood flow correlated with systolic blood pressure (r = -0.76, P < 0.01), LDL cholesterol (r = -0.62, P < 0.001), C-peptide (r = 0.65, P < 0.05), and triglycerides (r = 0.47, P < 0.05). CONCLUSIONS: These data suggest that neurogenic nociceptor-mediated vasodilation is impaired in subjects with type 2 diabetes when endothelial and sympathetic function are relatively intact. Heat-induced vasodilation may be a specific test of small heat-sensitive C-fiber peripheral neurons and may be an integral part of the metabolic syndrome.

Afferent Pathways↗