Glucose intolerance, metabolic syndrome, and neuropathy

doi:10.1016/B978-0-444-53480-4.00009-6

Handbook of Clinical Neurology

Volume 126, 2014, Pages 109-122

https://doi.org/10.1016/B978-0-444-53480-4.00009-6 Get rights and content

Abstract

There is increasing evidence that impaired glucose tolerance (IGT) or metabolic syndrome may result in peripheral nerve injury, although the exact relationship between the conditions is still being characterized. There is animal model, epidemiologic, and clinical evidence to suggest a pathophysiologic relationship between neuropathy and metabolic syndrome, along with its components including obesity, dyslipidemia, and insulin resistance. IGT and metabolic syndrome are associated with subclinical nerve damage or are typically painful and sensory predominant, although autonomic involvement may also occur. Because there is often preferential small fiber injury and nerve conduction studies may be relatively insensitive, skin biopsy with assessment of intraepidermal nerve fiber density is often used to confirm the diagnosis. Treatment of metabolic syndrome and IGT-associated neuropathies should include diet and exercise counseling, maintenance of normoglycemia, and targeted pharmacologic therapy for modifiable risk factors. Further research is required to fully elucidate the complex pathophysiology, as well as identify optimal diagnostic and treatment approaches.

Introduction

While peripheral neuropathy has traditionally been considered a late complication of diabetes, there is emerging evidence that it may be associated with clinical risk factors, particularly those associated with impaired glucose tolerance and metabolic syndrome. It is well recognized that macrovascular complications associated with diabetes develop at the “prediabetic” stage of impaired glucose tolerance (IGT), and evolving evidence suggests this may be true of peripheral neuropathy as well (Sumner et al., 2003, Pittenger et al., 2005). Metabolic syndrome, defined by a cluster of risk factors that occur together more often than by chance alone (Table 9.1), gained initial attention due to the increased risk of cardiovascular disease associated with the syndrome, producing a 10 year risk twice that of those without the syndrome (Alberti et al., 2009). Several metabolic syndrome components may be independent risk factors for the development of neuropathy, as well as direct mediators of pathogenesis. It is hypothesized that metabolic syndrome and its features are key independent risk factors for the development of neuropathy among subjects both with and without diabetes.

Section snippets

Hypotheses and pathophysiology

It is possible that the neuropathy observed with impaired glucose tolerance (IGT) simply represents a very early stage of diabetic neuropathy. However, the relationship is probably much more complex, involving the consequences of chronic obesity, lipotoxicity, and insulin resistance (Benton et al., 2008, Galuska et al., 2009, Zorzano et al., 2009a, Zorzano et al., 2009b). The extent to which IGT plays a direct role in the development of the macro- and microvascular complications of diabetes is

Definition and prevalence of metabolic syndrome

Metabolic syndrome (also previously known as syndrome X or insulin resistance syndrome) consists of several features, initially identified due to their association with type 2 diabetes and cardiovascular disease (Ford et al., 2002). The most recent diagnostic criteria have been established in a consensus statement from the International Diabetes Federation Task Force on Epidemiology and Prevention, the National Heart, Lung and Blood Institute, the American Heart Association, the World Heart

Epidemiology

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are both terms used to describe intermediate abnormalities in glucose handling. Both are encompassed by the term “prediabetes.” Prediabetes is common, with the most recent US epidemiologic data indicating that during the period 1988–1994, among US adults ages 40–74 years, 15.4% had IGT and 40.1% had prediabetes (IGT or IFG or both) (National Institute of Diabetes and Digestive and Kidney Diseases, 2010, Harris et al., 1998).

Obesity and dyslipidemia

Several features of metabolic syndrome have been linked to neuropathy, particularly obesity and dyslipidemia, independent of hyperglycemia (Herman et al., 2007, Smith et al., 2008). The largest studies have examined metabolic syndrome contribution to neuropathy risk in patients with known diabetes. In a cross-sectional study of 548 type 2 diabetic subjects, 85% had metabolic syndrome; those meeting criteria for metabolic syndrome were twice as likely to have a distal sensory neuropathy (44%

Clinical presentation of impaired glucose tolerance and metabolic syndrome-associated neuropathy

Clinically evident neuropathy occurring in early diabetes is characterized by preferential injury to small nerve fibers, and sensory symptoms, including pain and autonomic dysfunction. In a survey of 669 patients with early diabetic neuropathy, > 60% reported sensory symptoms, 40% impotence, 33% other autonomic dysfunction, but just 12% had motor involvement (Thomas, 1997). It has been noted that cold sensation, a small fiber function, is frequently involved prior to vibratory sensation, a large

Laboratory testing for glucose dysmetabolism

The prediabetic state is defined by the American Diabetes Association as an abnormal glucose in the fasting state (impaired fasting glucose (IFG)), or impaired glucose tolerance after an abnormal standardized 2 hour oral glucose tolerance test (OGTT) using 75 grams of oral dextrose. IFG is considered present when a fasting glucose level is 100–125 mg/dL (5.6–6.9 mmol/L). IGT is defined as a 2 hour glucose level after OGTT of 140–199 mg/dL (7.8–11.0 mmol/L) (American Diabetes Association, 2010). In

Overview of ancillary testing

Several reports have suggested that IGT-associated neuropathy may present as primarily a small fiber neuropathy. A study of 97 patients with idiopathic neuropathy compared characteristics of those with IGT versus those with diabetes. Those with IGT were more likely to have neuropathy that was restricted to small nerve fibers (Sumner et al., 2003). Similarly, a study utilizing skin biopsy to assess six patients with IGT, eight with early diabetes, and five controls, showed that neuropathy

Outcomes and prognosis

The long-term prognosis for patients with IGT and metabolic syndrome-related neuropathies is largely unknown, though it is expected to parallel that of early diabetic neuropathy. Clinical experience suggests that these patients will experience a gradual, slow progression over time. If left untreated, there is an increased relative risk of progression (RR of 6.3) from IGT to overt diabetes within 1 year (Gerstein et al., 2007). While the rate of progression of neuropathy in IGT/metabolic

Glucose control

Intuitively, the treatment of IGT neuropathy should mirror management of diabetic peripheral neuropathy, which has traditionally focused on control of hyperglycemia. The impact of intensive glycemic control on diabetic peripheral neuropathy has been widely evaluated, but with conflicting results. Several studies, including the Diabetes Control and Complications Trial (DCCT), have demonstrated that intensive glycemic control delayed the onset and progression of clinically confirmed neuropathy,

Future directions

While the Impaired Glucose Tolerance Neuropathy (IGTN) Study demonstrated improvement in small fiber neuropathy measures at 1 year, these gains were not sustained (Smith and Singleton, 2008). Despite continued improvement of weight, glycemic control, and lipid parameters, measures of neuropathy severity (and especially large fiber measures) progressed over 3 years, suggesting earlier and/or more aggressive interventions are needed. Research is ongoing regarding approaches to this complex

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Although fructose did not increase SUA level, it did impair glucose tolerance as in the Uox−/− group, indicating that fructose is more likely to induce metabolic syndrome rather than hyperuricemia. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are both encompassed by the term “prediabetes” [38]. Therefore, hyperuricemia induced IGT and IFG may be an important mechanism related to other metabolic diseases.
Hyperuricemia animal models have long been used for evaluating food-derived anti-hyperuricemia compounds. Fructose and potassium oxonate are commonly used for developing hyperuricemia mouse model. Recent research also developed spontaneous hyperuricemia model by uricase knockout (Uox^−/−). In this work, we evaluated 3 kinds of models with the same gene background to illustrate the differences between the treatments. Unlike the uric acid levels in potassium oxonate (224.79 ± 33.62 μmol/L) and Uox^−/− groups (458.39 ± 38.29 μmol/L), fructose treatment did not lead to higher serum uric acid level (174.93 ± 30.46 μmol/L) comparing to the control group (153.53 ± 40.96 μmol/L). However, abnormal glycometabolism only developed in the fructose and the Uox^−/− group. In addition, anemia, inflammasome and severe renal injury occurred in the Uox^−/− group. The Uox^−/− mice were then treated with puerarin and allopurinol, and found that puerarin could reduce serum uric acid and alleviated the serious renal damage associated with high uric acid. Thus, the Uox^−/− mice could be a suitable model for screening and evaluating anti-hyperuricemia compounds.
Translating a treatment for diabetic peripheral neuropathy from rodents to humans: Can a case be made for fish oil and salsalate?
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According to the American Diabetes Association, in 2015, 9.4% of the United States population had diabetes and statistically, about 50% of these patients will or already have developed peripheral neuropathy. Furthermore, peripheral neuropathy is detectable in about 30% of subjects with prediabetes and impaired glucose tolerance. The only treatment recognized for diabetic peripheral neuropathy (DPN) is glycemic control, which slows progression in patients with type 1 diabetes but is less effective in subjects with type 2 diabetes. With the occurrence of obesity and type 2 diabetes at epidemic levels, there is a critical need of treatment. In this chapter, I will focus on data from my laboratory and others of the potential for omega-3 polyunsaturated fatty acids naturally enriched in fish oil combined with salsalate as a safe and efficacious treatment for DPN.
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La neuropatía diabética (ND) es una de las formas más frecuentes de afectación microvascular de los pacientes diabéticos. Es un conjunto heterogéneo de formas clínicas con diversas manifestaciones. Las complicaciones se relacionan con el tiempo de evolución de la diabetes y el grado de hiperglucemia. Su sintomatología puede pasar desapercibida durante años, de manera que su detección recaerá en el profesional que evalúe al paciente. La ND posee varias formas clínicas que incluyen: polineuropatía simétrica distal, neuropatía autonómica, radiculopatía amioatrófica, mononeuropatía simple y mononeuropatía múltiple. La polineuropatía sensitiva simétrica es la presentación más habitual, caracterizada por una pérdida gradual de la sensibilidad distal y de la propiocepción articular y por un ascenso del umbral del dolor que puede contribuir a la aparición de complicaciones como la formación de úlceras, alteraciones musculares o la deformidad de Charcot. Su cribado debe realizarse en el momento del diagnóstico en los pacientes con diabetes mellitus (DM) tipo 2 y a los 5 años del diagnóstico de la DM tipo 1, siendo revaluados anualmente. El control glucémico adecuado parece disminuir la prevalencia en pacientes diabéticos tipo 1 y enlentecer la progresión, pero sin evitar la pérdida neuronal en los diabéticos tipo 2. El resto de las medidas terapéuticas aportan control sintomático con resultados variables.
Diabetic neuropathy (DN) is one of the commonest microvascular complication of diabetic patient. It is a heterogeneous group of disorders with distinct clinical features. Complications are proportional to both the magnitude and duration of hyperglycemia. Because symptomatology may go unnoticed for years, a good assessment will facilitate its detection. DN may manifest in several different forms: distal symmetric polyneuropathy, autonomic neuropathy, amyotrophic radiculopathy, mononeuropathy simplex and multiplex. Sensorimotor distal symmetric polyneuropathy is the most common form of neuropathy in diabetes. Typically, patients experience gradual distal numbness and joint proprioception and an increase in the pain threshold, triggering complications such as ulcers, muscle disorders or Charcot deformity. DN screening has to be performed in the moment of diagnosis (type 2 diabetes mellitus –DM–), and 5 years after diagnosis (type 1 DM); revaluation must be annual. In type 1 diabetic patients, glycemic control reduces the prevalence of DN and delay its progression; however, in type 2 neuronal loss cannot be avoided. Remaining therapeutic options are symptomatic with variable results.
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The leading cause of peripheral neuropathy in the United States is diabetes affecting approximately 60% of individuals with type 2 diabetes (T2D) and 30% of individuals with prediabetes. Neuropathy associated with diabetes or prediabetes manifests with distal symmetric polyneuropathy (Callaghan, Price, & Feldman, 2015; Cortez, Singleton, & Smith, 2014; O'Brien, Hinder, Callaghan, & Feldman, 2017; Tabak, Herder, Rathmann, Brunner, & Kivimaki, 2012) and exhibits a “stocking and glove” pattern of progressive peripheral sensory nerve loss characterized by pain, numbness, and eventual loss of sensation. Little is known about the biological pathways that underlie the onset and progression of neuropathy in diabetes and prediabetes (O'Brien et al., 2017; O'Brien, Hinder, Sakowski, & Feldman, 2014; Vas & Edmonds, 2016; Zochodne, 2014).
Peripheral neuropathy is a common and debilitating complication of diabetes and prediabetes. Recent clinical studies have identified an association between the development of neuropathy and dyslipidemia in prediabetic and diabetic patients. Despite the prevalence of this complication, studies identifying molecular mechanisms that underlie neuropathy progression in prediabetes or diabetes are limited. However, dysfunctional mitochondrial pathways in hereditary neuropathy provide feasible molecular targets for assessing mitochondrial dysfunction in neuropathy associated with prediabetes or diabetes. Recent studies suggest that elevated levels of dietary saturated fatty acids (SFAs) associated with dyslipidemia impair mitochondrial dynamics in sensory neurons by inducing mitochondrial depolarization, compromising mitochondrial bioenergetics, and impairing axonal mitochondrial transport. This causes lower neuronal ATP and apoptosis. Conversely, monounsaturated fatty acids (MUFAs) restore nerve and sensory mitochondrial function. Understanding the mitochondrial pathways that contribute to neuropathy progression in prediabetes and diabetes may provide therapeutic targets for the treatment of this debilitating complication.
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Dyslipidemia associated with T2D leads to diabetic neuropathy, a complication characterized by sensory neuronal dysfunction and peripheral nerve damage. Sensory dorsal root ganglion (DRG) neurons are dependent on axonal mitochondrial energy production facilitated by mitochondrial transport mechanisms that distribute mitochondria throughout the axon. Because long-chain saturated FAs (SFAs) damage DRG neurons and medium-chain SFAs are reported to improve neuronal function, we evaluated the impact of SFA chain length on mitochondrial trafficking, mitochondrial function, and apoptosis. DRG neurons were exposed to SFAs with C12:0−C18:0 chain lengths and evaluated for changes in mitochondrial trafficking, mitochondrial polarization, and apoptosis. DRG neurons treated with C16:0 and C18:0 SFAs showed a significant decrease in the percentage of motile mitochondria and velocity of mitochondrial trafficking, whereas C12:0 and C14:0 SFAs had no impact on motility. Treatment with C16:0 and C18:0 SFAs exhibited mitochondrial depolarization correlating with impaired mitochondrial motility; the C12:0- and C14:0-treated neurons retained mitochondrial polarization. The reduction in mitochondrial trafficking and function in C16:0- and C18:0-treated DRG neurons correlated with apoptosis that was blocked in C12:0 and C14:0 SFA treatments. These results suggest that SFA chain length plays an important role in regulating axonal mitochondrial trafficking and function in DRG neurons.
Value-Added Electrodiagnostics: Targeting Interventions for Fall Risk Reduction
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In fact, patient populations with arguably the greatest need for the therapeutic effects of walking harbor greater risk of falling. Neuropathy is a well-established risk factor for falls,7 and it is associated with type 2 diabetes mellitus as well as the metabolic syndrome8,9—both conditions for which walking and exercise are recommended. Without exercise, a vicious cycle ensues, in which diminished peripheral nerve function can lead to diminished activity, which may, in turn, raise risk factors for neuropathy (Fig. 1).

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Chapter 9 - Glucose intolerance, metabolic syndrome, and neuropathy

Abstract

Introduction

Section snippets

Hypotheses and pathophysiology

Definition and prevalence of metabolic syndrome

Epidemiology

Obesity and dyslipidemia

Clinical presentation of impaired glucose tolerance and metabolic syndrome-associated neuropathy

Laboratory testing for glucose dysmetabolism

Overview of ancillary testing

Outcomes and prognosis

Glucose control

Future directions

Diabetes Metab

J Diabetes Complications

J Diabetes Complications

J Diabetes Complications

Diabetes Metab

Pharmacol Res

Lancet

Diabetes Res Clin Pract

Metabolism

Eur J Pharmacol

Lancet

Diabetes Res Clin Pract

Biochim Biophys Acta

J Am Coll Cardiol

Metabolism

Neurobiol Dis

Neurobiol Dis

J Neurol Sci

J Neurol Sci

Impaired glucose tolerance: what are the clinical implications?

Diabetes Res Clin Pract

Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation

Diabet Med

Circulation

Standards of medical care in diabetes – 2010

Diabetes Care

Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts

BMC Neurol

Expression of Mfn2, the Charcot–Marie–Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6

Diabetes

Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older women and men. The Rancho Bernardo Study

Diabetes Care

PGC-1alpha-mediated regulation of gene expression and metabolism: implications for nutrition and exercise prescriptions

Appl Physiol Nutr Metab

The 6th Annual World Congress on the Insulin Resistance Syndrome

Diabetes Care

Expression of mitofusin 2(R94Q) in a transgenic mouse leads to Charcot–Marie–Tooth neuropathy type 2A

Brain

Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in type 2 diabetes

Diabet Med

Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey 1999–2002

Diabetes Care

Diet-induced obesity in Sprague-Dawley rats causes microvascular and neural dysfunction

Diabetes Metab Res Rev

Impaired glucose tolerance and fasting hyperglycaemia have different characteristics

Diabet Med

Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria

Arch Intern Med

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus

N Engl J Med

Does impaired glucose metabolism cause polyneuropathy? Review of previous studies and design of a prospective controlled population-based study

Muscle Nerve

Diabetes regulates mitochondrial biogenesis and fission in mouse neurons

Diabetologia

Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003–2006

Natl Health Stat Report

Mediterranean diet and the metabolic syndrome: the end of the beginning

Metab Syndr Relat Disord

Diabetes, lipids, and adipocyte secretagogues

Biochem Cell Biol

Pathogenesis of diabetic neuropathy

Clin Neurosci

Cross-talk between iron metabolism and diabetes

Diabetes

Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey

JAMA