Ann M. Poynten

Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content.

Insulin resistance is associated with increased circulating lipids and skeletal muscle lipid content. Chronic nicotinic acid (NA) treatment reduces insulin sensitivity and provides a model of insulin resistance. We hypothesized that the reduction in insulin sensitivity occurs via elevation of circulating nonesterified fatty acids (NEFAs) and an increase in intramyocellular lipid (IMCL). A total of 15 nondiabetic males (mean age 27.4 +/- 1.6 years) were treated with NA (500 mg daily for 1 week, 1 g daily for 1 week). Insulin sensitivity (glucose infusion rate [GIR]) was determined pre- and post-NA by euglycemic-hyperinsulinemic clamp. Substrate oxidation was determined by indirect calorimetry. Skeletal muscle lipid was assessed by estimation of long-chain acyl-CoA (LCACoA) and triglyceride (TG) content and by (1)H-magnetic resonance spectroscopy quantification of IMCL (n = 11). NA reduced GIR (P =.03) and nonoxidative glucose disposal (P <.01) and increased fasting NEFAs (P =.01). The decrease in GIR related significantly to the increase in fasting NEFAs (r(2) =.30, P =.03). The intrasubject increase in basal and clamp fat oxidation correlated with the decrease in GIR (r(2) =.45, P <.01 and r(2) =.63, P <.01). There were no significant changes in muscle LCACoA, TG, or IMCL content. Therefore, induction of insulin resistance by NA occurs with increased availability of circulating fatty acids to muscle rather than with increased muscle lipid content.

Relationship of adiponectin with insulin sensitivity in humans, independent of lipid availability

Objective: To test in humans the hypothesis that part of the association of adiponectin with insulin sensitivity is independent of lipid availability.

Fat oxidation, body composition and insulin sensitivity in diabetic and normoglycaemic obese adults 5 years after weight loss

OBJECTIVE: To investigate whether normal glucose-tolerant and type II diabetic overweight adults differ in response to weight regain with regard to substrate oxidation and metabolic parameters.METHODS: A total of 15 overweight-obese subjects: seven normal glucose tolerant (NGT) and eight with type II diabetes (DM) were restudied 5 y after significant weight loss. Prediet, after 28 days calorie restriction and at 5 y, subjects were characterised for weight, height, waist-to-hip ratio (WHR) and body composition by dual-energy X-ray absorptiometry. Fasting glucose, insulin, leptin and lipid levels were measured and subjects underwent euglycaemic–hyperinsulinaemic clamp (insulin 0.25 U/kg/h for 150 min). Indirect calorimetry was performed resting and in the final 30 min of the clamp. Dietary assessment was by 4-day diet-diary.RESULTS: Both NGT and DM groups regained weight at 5 y and were not different to prediet. Total body fat (%) and WHR were higher at 5 y compared to prediet in both groups. Fasting glucose was increased in NGT subjects at 5 y, and fasting insulin was higher in both groups at 5 y compared to prediet. Insulin sensitivity (GIR) was similar at 5 y compared to prediet, but at 5 y DM subjects were more insulin resistant than NGT subjects. At 5 y, both DM and NGT groups had significantly reduced basal fat oxidation and no significant suppression of fat oxidation with insulin. Clamp respiratory quotient levels at 5 y were significantly higher in NGT compared to DM subjects.CONCLUSION: Reduced basal fat oxidation, and reduced variation in substrate oxidation in response to insulin develop with fat regain and fasting hyperinsulinaemia in both NGT and DM obese adults.

Effects of Axonal Ion Channel Dysfunction on Quality of Life in Type 2 Diabetes

OBJECTIVE Pharmacological agents for diabetic peripheral neuropathy (DN) target a number of mechanisms, including sodium channel function and γ-aminobutyric acid–minergic processes. At present, prescription is undertaken on a trial-and-error basis, leading to prolonged medication trials and greater healthcare costs. Nerve-excitability techniques are a novel method of assessing axonal ion channel function in the clinical setting. The aim of this study was to determine the effects of axonal ion channel dysfunction on neuropathy-specific quality-of-life (QoL) measures in DN. RESEARCH DESIGN AND METHODS Fifty-four patients with type 2 diabetes mellitus underwent comprehensive neurologic assessment, nerve-conduction studies, and nerve-excitability assessment. Neuropathy severity was assessed using the Total Neuropathy Score. Neuropathy-specific QoL was assessed using a DN-specific QoL questionnaire (Neuropathy-Specific Quality of Life Questionnaire [NeuroQoL]). Glycosylated hemoglobin and BMI were recorded in all patients. RESULTS NeuroQoL scores indicated significant QoL impairment (mean 9.08 ± 5.93). Strength-duration time constant (SDTC), an excitability parameter reflecting sodium channel function, was strongly correlated with QoL scores (r = 0.545; P < 0.005). SDTC was prolonged in 48.6% of patients who experienced neuropathic symptoms. A significant correlation was also noted between SDTC and neuropathy severity (r = 0.29; P < 0.05). This relationship was strengthened when looking specifically at patients with clinically graded neuropathy (r = 0.366; P < 0.05). CONCLUSIONS The current study has demonstrated an association between markers of sodium channel function and QoL in DN. The study demonstrates that excitability techniques may identify patients in whom altered sodium channel function may be the dominant abnormality. The findings suggest that excitability techniques may have a role in clinical decision making regarding neuropathic treatment prescription.

Axonal dysfunction prior to neuropathy onset in type 1 diabetes

The present study was undertaken to determine whether there were changes evident in axonal membrane function prior to the onset of neuropathy in patients with type 1 and type 2 diabetes.

A Case of Hemichorea-Hemiballismus Due to Nonketotic Hyperglycemia

Nonketotic hyperglycemia is a rare cause of hemichorea-hemiballismus. It is more common among postmenopausal woman and can be the first presentation of diabetes mellitus (1). This case report illustrates the importance of distinguishing this cause from other intracranial pathologies as prompt glycemic control leads to complete resolution of the symptoms and signs. A 76-year-old female presented to our emergency department following a 24-h history of involuntary right upper- and lower-limb movements. There was no history of stroke or preceding trauma. Her neurological examination was notable for right-sided periodic choreiform and ballistic movements, which improved during sleep. Initial biochemistry revealed a blood glucose of 24.4 mmol/L (439.6 mg/dL), normal venous pH (7.37), and negative blood ketones (<0.5 mmol/L). Her HbA1c was 17.3% …

Islet-1: A potentially important role for an islet cell gene in visceral fat

Objective: To examine differences in gene expression between visceral (VF) and subcutaneous fat (SF) to identity genes of potential importance in regulation of VF.

Continuous subcutaneous insulin infusion preserves axonal function in type 1 diabetes mellitus.

Diabetic peripheral neuropathy is a common and debilitating complication of diabetes mellitus. Although strict glycaemic control may reduce the risk of developing diabetic peripheral neuropathy, the neurological benefits of different insulin regimens remain relatively unknown.

In vivo evidence of reduced nodal and paranodal conductances in type 1 diabetes.

OBJECTIVES Diabetic neuropathy is a debilitating complication of diabetes. Animal models of type 1 diabetes (T1DM) suggest that functional and structural changes, specifically axo-glial dysjunction, may contribute to neuropathy development. The present study sought to examine and characterise early sensory axonal function in T1DM patients in the absence of clinical neuropathy. METHODS Thirty patients with T1DM (15M:15F) without neuropathy underwent median nerve sensory and motor axonal excitability studies to examine axonal function. A verified mathematical model of human motor and sensory axons was used to elucidate the underlying causes of observed alterations. RESULTS Compared to controls (NC), T1DM patients demonstrated significant axonal excitability abnormalities in sensory and motor axons. These included marked reductions in sensory and motor subexcitability during the recovery cycle (T1DM 7.9 ± 0.4:10.4 ± 0.6%, NC 10.4 ± 0.7:15.4 ± 1.2%, P<0.01) and during hyperpolarizing threshold electrotonus at 10-20 ms (T1DM -75.5 ± 0.8:-69.7 ± 0.8%, NC -78.4 ± 1:-72.7 ± 0.9%, P<0.01). Mathematical modelling demonstrated that these changes were due to reduced nodal Na(+) currents, nodal/paranodal K(+) conductances and Na(+)/K(+) pump dysfunction, consistent with axo-glial dysjunction as outlined in animal models of T1DM. CONCLUSIONS The study provided support for the occurrence of early changes in nodal and paranodal conductances in patients with T1DM. SIGNIFICANCE These data indicate that axonal excitability techniques may detect early changes in diabetic patients, providing a window of opportunity for prophylactic intervention in T1DM.

Association between glycemic variability and peripheral nerve dysfunction in type 1 diabetes

Introduction: Glycemic variability (GV) may be a novel factor in the pathogenesis of diabetic complications. However, the effect of GV on peripheral nerve function has not been explored systematically. Methods: The relationship between GV and acute glucose levels on motor and sensory nerve function in 17 patients with type 1 diabetes mellitus (T1DM) was assessed using continuous glucose monitoring and nerve excitability techniques to provide insight into the behavior of axonal voltage‐gated ion channels. The mean amplitude of glycemic excursions (MAGE) was calculated to quantify GV. Results: MAGE strongly correlated with excitability markers of altered motor and sensory axonal function, including superexcitability (r = 0.54), S2 accommodation (r = ‐0.76), minimum current threshold (I/V) slope (r = 0.71), strength duration time constant (r = 0.66), and latency (r = 0.65; P <  0.05). Acute glucose levels did not correlate with markers of axonal function. Conclusions: These findings suggest that GV may be an important mediator of axonal dysfunction in T1DM and a contributing factor in development of diabetic neuropathy. Muscle Nerve, 2016 Muscle Nerve 54: 967–969, 2016