Current Diabetes Reviews

ISSN: 1573-3998

Current Diabetes Reviews
Volume 2, Number 3, August 2006

Contents


Uncoupling Proteins: Role in Insulin Resistance and Insulin Insufficiency Pp. 271-283
Catherine B. Chan and Mary-Ellen Harper
[Abstract]


Barriers to Achieving Optimal Glycemic Control in a Multi-Ethnic Society: A US Focus Pp. 285-293
Samuel Dagogo-Jack, Martha M. Funnell and Jaime Davidson
[Abstract]


The Role Played by Serine Proteases in the Development and Worsening of Vascular Complications in Type 1 Diabetes Mellitus Pp. 295-305
Paola Finotti
[Abstract]


Metformin Beyond Diabetes: New Life for an Old Drug Pp. 307-315
Carlo M. Rotella, Matteo Monami and Edoardo Mannucci
[Abstract]


Interactions of Endothelin and Insulin: Expanding Parameters of Insulin Resistance Pp. 317-327
Andrew B. Strawbridge, Jeffrey S. Elmendorf and Kieren J. Mather
[Abstract]


Baroreflex Function: Determinants in Healthy Subjects and Disturbances in Diabetes, Obesity and Metabolic Syndrome Pp. 329-338
Ioanna Skrapari, Nicholas Tentolouris and Nicholas Katsilambros
[Abstract]


Theraputic Management Strategies for Type 2 Diabetes Pp. 339-342
C. Ramesh, V. Gopal, K. Sembulingam and M. Nappinnai
[Abstract]


Diagnosis and New Approaches in the Therapy of Gestational Diabetes Mellitus Pp. 343-352
Ute M. Schaefer-Graf and Helmut Kleinwechter
[Abstract]


Diagnostic Tools for Diabetic Sensorimotor Polyneuropathy Pp. 353-361
Keri A. Kles and Vera Bril
[Abstract]


The Role of PTB in Insulin mRNA Stability Control Pp. 363-366-
Rickard G. Fred, Linda Tillmar and Nils Welsh
[Abstract]




Abstracts

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Uncoupling Proteins: Role in Insulin Resistance and Insulin Insufficiency
Catherine B. Chan and Mary-Ellen Harper

Uncoupling proteins (UCPs) are modulators of mitochondrial metabolism that have been implicated in the development of both insulin resistance and insulin insufficiency, the two major pathophysiological events associated with type 2 diabetes. UCP2 mRNA is expressed in a wide range of tissues; however UCP2 protein expression is restricted to fewer tissues, including the endocrine pancreas, spleen, stomach, brain and the lung. To date, its role in the pathophysiology of diabetes has been most strongly associated with impaired glucose-stimulated insulin secretion from the β-cell, particularly after its induction by free fatty acids. The physiological role of UCP2 remains controversial, but it may act as a downstream signal transducer of superoxide. UCP3 mRNA and protein are expressed in relatively few tissues, predominately skeletal muscle, brown adipose tissue and heart. Increased expression of UCP3 in skeletal muscle is associated with protection from diet-induced insulin resistance in mice. In patients with type 2 diabetes UCP3 protein in muscle is reduced by 50% compared to healthy controls. The primary physiological role of the novel UCPs does not appear to be protection against positive energy balance and obesity; this is based largely on findings from studies of UCP2 and UCP3 knockout mice and from observed increases in UCP3 expression with fasting. The mechanism(s) of action of UCP2 and UCP3 are poorly understood. However, findings support roles for UCP2 and UCP3 as modifiers of fatty acid metabolism and in mitigating damage from reactive oxygen species.


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Barriers to Achieving Optimal Glycemic Control in a Multi-Ethnic Society: A US Focus
Samuel Dagogo-Jack, Martha M. Funnell and Jaime Davidson

The increasing prevalence of diabetes is particularly apparent in certain ethnic groups, such as African and Hispanic Americans. These groups generally also have poorer glycemic control and outcomes. To better understand the issues surrounding these problems and possible methods to overcome them we performed a literature review from the past 15 years on barriers to glycemic control with a focus on US data. The literature reveals that barriers may be inherent (eg, genetic, cultural, and language/communication) or acquired (eg, those associated with changes in lifestyle and socioeconomic factors). Healthcare interventions that take into consideration cultural and population-specific characteristics can reduce the prevalence and severity of diabetes and its resulting complications. Implementing such strategies will require suitable education for patients and providers, the availability of culturally-sensitive, patient-centered healthcare teams, the creation of collaborative relationships between providers and patients, better use of community resources, and assistance for patients to make informed decisions about available treatment options. There is also evidence suggesting that at the same level of glucose control Hispanics and African Americans have the same degree of complications as whites; therefore, good control is essential for the future well-being of all patients. Addressing these issues may help to decrease the ethnic disparities that currently exist in diabetes care.


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The Role Played by Serine Proteases in the Development and Worsening of Vascular Complications in Type 1 Diabetes Mellitus
Paola Finotti

Much attention has been given to the role played by serine proteases in the development and worsening of vascular complications in Type 1 diabetes mellitus. A generalized increase in proteolytic activity, either due to a true increase in concentration of specific proteases or defects of their protease inhibitors, represents an early marker of diabetes. However, the precise molecular mechanism whereby an unopposed proteolytic activity leads to overt vascular alterations has not fully been elucidated as yet. The picture is further complicated by the fact that, although sharing the same function, serine proteases constitute a structurally heterogeneous class of molecules. Besides classical proteases, for most part belonging to coagulative and fibrinolytic systems, other unrelated molecules exhibit serine-like protease activity and are capable of triggering both inflammatory and immune reactions. The specific role of these non classical serine proteases in the complex pathogenesis of diabetes and its vascular complications is attracting a new investigative interest, as these molecules may represent additional therapeutic targets. This review will focus on most recent acquisitions on this issue relevant to Type 1 diabetes.


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Metformin Beyond Diabetes: New Life for an Old Drug
Carlo M. Rotella, Matteo Monami and Edoardo Mannucci

Metformin is a widely used drug in the therapy of patients affected by diabetes mellitus. Although some caution is needed in the very old, advanced age per se does not represent a contraindication to metformin use. Despite the fact that its precise mechanism of action it is not completely elucidated, long-term treatment with this drug in monotherapy, improves glycaemic control and reduces cardiovascular mortality in overweight type 2 diabetic patients. Experimental evidence produced over the years suggests that metformin may be useful in some clinical conditions different from diabetes mellitus.

In the present review we have examined currently available data about the possible use of metformin as an effective therapeutical agent in pathological conditions different from type 2 diabetes mellitus. On the basis of our investigation, the use of metformin can be suggested in overweigth patients affected by impaired glucose tolerance and/or fasting hyperglycaemia and in subjects affected by polycystic ovary syndrome, while further data are needed in order to prescribe such a drug in patients affected by non-alcoholic steato-hepatitis and in HIV patients on antiretroviral therapy.


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Interactions of Endothelin and Insulin: Expanding Parameters of Insulin Resistance
Andrew B. Strawbridge, Jeffrey S. Elmendorf and Kieren J. Mather

Since the discovery of endothelin peptides in the mid-1980s by Yanigasawa and colleagues, accumulating evidence demonstrates that these peptides may function beyond vasoconstriction. Strong epidemiologic associations between insulin resistance and increased endothelin levels or activity have been found, and these associations have prompted studies investigating the interactions of endothelin with insulin. In this review we explore the evidence for such interactions at multiple levels of physiology, ranging from effects on tissue perfusion through modulation of vascular tone to subcellular interactions of endothelin signaling with insulin signaling. The evidence implicating endothelin in insulin resistance and its associated vascular and metabolic abnormalities is reviewed.


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Baroreflex Function: Determinants in Healthy Subjects and Disturbances in Diabetes, Obesity and Metabolic Syndrome
Ioanna Skrapari, Nicholas Tentolouris and Nicholas Katsilambros

Arterial baroreceptors play an important role in the short-term regulation of arterial pressure, by reflex chronotropic effect on the heart and by reflex regulation of sympathetic outflow. Baroreflex sensitivity (BRS) represents an index of arterial baroreceptors function. Several methods of measuring BRS are available nowadays. Different factors influence BRS in the healthy population, including sex, age, blood pressure, heart rate, body fatness, arterial stiffness, blood glucose and insulin levels, as well as physical activity. Baroreceptors dysfunction is evident in diseases such as coronary artery disease, heart failure, arterial hypertension, diabetes mellitus and obesity. The underlying mechanism of BRS attenuation in diabetes or obesity is not yet well known; however, there is increasing evidence that it is at least partly related to autonomic nervous system dysfunction and particularly to sympathetic overactivity that accompanies these diseases. Blunted BRS provides prognostic information for cardiovascular diseases and possibly for diabetes, while its’ prognostic information for obesity is not yet established. This review deals with the mechanisms affecting baroreflex function, the newer techniques of BRS estimation and the most recent insights of baroreflex function in the healthy population and in various diseases with emphasis on diabetes and obesity. In addition, the clinical implication of a reduced BRS in these disorders is discussed.


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Theraputic Management Strategies for Type 2 Diabetes
C. Ramesh, V. Gopal, K. Sembulingam and M. Nappinnai

Diabetes mellitus type 1 and 2 affects people worldwide and is associated with further complications like macrovascular, microvascular and its effect is observed as retinopathy, cardiovascular diseases, nephropathy and many more diseases. There are numerous suggestions, treatments for presentation and controlling diabetes but no curative agents. Therefore the aim is to prevent or delay onset or control the complications. This work outlines the principle strategies for management of type 2 diabetes.


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Diagnosis and New Approaches in the Therapy of Gestational Diabetes Mellitus
Ute M. Schaefer-Graf and Helmut Kleinwechter

Gestational diabetes mellitus (GDM) is one of the most common complications in pregnancy. It affects 3-15% of women, depending on the background diabetes risk of the population and applied diagnostic criteria. GDM is associated with neonatal problems such as macrosomia and neonatal hypoglycemia as well as a long term increased risk of diabetes and obesity of offspring. Current therapy of GDM focuses on tightly controlling maternal glucose levels, resulting in insulin therapy in up to 50% of women to reach the fasting glucose target of< 90 mg/dl and 2h-postprandial glucose < 120 mg/dl. However, the rate of macrosomia and C-sections remains increased in pregnancy with GDM despite therapy.

This review introduces the diagnosis and implications of GDM and then examines two strands of research aimed at improving current therapy: first, research into predictive markers of GDM pregnancies requiring intensified insulin therapy, and second, research into hypoglycaemic agents for therapy or even prevention of GDM in high risk women such as women with polycystic ovarian syndrome.

Predictive markers include amniotic fluid insulin, which requires an invasive amniocentesis procedure, and measures of fetal abdominal circumference early in the third trimester, which have successfully been used to reduce rates of macrosomia.

Potential hypoglycemic agents include glyburides and metformin, which have been shown not to have adverse outcomes on neonates, although oral agents are generally contra-indicated because of possible teratogenic and toxic effects observed in animal studies and missing long term outcome data.


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Diagnostic Tools for Diabetic Sensorimotor Polyneuropathy
Keri A. Kles and Vera Bril

Diabetes and its complications are major causes of mortality in the United States, with increasing rates of morbidity and increasing health care costs. Patients diagnosed with diabetes attempt to control cholesterol levels, blood pressure, and blood glucose levels to decrease the risk of diabetic microvascular complications (DMC), such as diabetic sensorimotor polyneuropathy (DSP) [also known as diabetic peripheral neuropathy (DPN)]. Despite control of these risk factors for vascular disease, many patients still develop DSP. Research investigating diabetic neuropathy holds promise for specific treatment of diabetic complications. Intrinsic to the success of new therapies is the accurate diagnosis and evaluation of DSP. Symptom scores, quantitative sensory testing and electrophysiology are some of the diagnostic tools to identify the signs and symptoms of DSP. Early detection of neuropathy enables clinicians to prevent long-term complications like ulcers and amputations in patients with diabetes. The focus of this review is to describe the composite of tools necessary for diagnosis of DSP.


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The Role of PTB in Insulin mRNA Stability Control
Rickard G. Fred, Linda Tillmar and Nils Welsh

Although extensively studied, there are still many unanswered questions regarding the regulation of insulin gene expression. This is important to further investigate since it will help us understand the pathophysiology of some types of diabetes. The insulin mRNA has a long half-life and changes in insulin mRNA stability, induced by glucose, are likely to be regulated through specific mechanisms. Recent findings indicate that the polypyrimidine tract binding protein (PTB), also named hnRNP I, by binding to the 3'-UTR (untranslated region) of the insulin mRNA molecule, stabilizes the messenger thereby participating in the glucose-induced increase in insulin mRNA. This review will focus on recent findings pertinent to PTB subcellular localization and function. It appears that PTB shuttles between the nucleus and the cytosol, and that protein kinase A (PKA)-mediated PTB phosphorylation promotes PTB translocation to the cytosol, an event that might enhance insulin mRNA stability. We will also review beta-cell signaling events that may control the mRNA stabilizing effect of PTB.