Mamta Jaiswal

Peripheral Neuropathy in Adolescents and Young Adults With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-Up Cohort A pilot study

OBJECTIVE To estimate the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in a pilot study among youth participating in the SEARCH for Diabetes in Youth study. RESEARCH DESIGN AND METHODS DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI) (examination for foot abnormalities, distal vibration perception, and ankle reflexes). An MNSI exam (MNSIE) score >2 is diagnostic for DPN. RESULTS The MNSIE was completed in 399 subjects, including 329 youth with type 1 diabetes (mean age 15.7 ± 4.3 years, duration 6.2 ± 0.9 years) and 70 with type 2 diabetes (mean age 21.6 ± 4.1 years, duration 7.6 ± 1.8 years). Glycated hemoglobin (A1C) was similar in both groups (8.8 ± 1.8% for type 1 vs. 8.5 ± 2.9% for type 2). The prevalence of DPN was significantly higher in youth with type 2 compared with those with type 1 diabetes (25.7 vs. 8.2%; P < 0.0001). In unadjusted analyses, diabetes type, older age, longer duration of diabetes, increased waist circumference, elevated blood pressure, lower HDL cholesterol, and presence of microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) were associated with DPN. The association between diabetes type and DPN remained significant after adjustment for age and sex (odds ratio 2.29 [95% CI 1.05–5.02], P = 0.03). CONCLUSIONS DPN prevalence among youth with type 2 diabetes approached rates reported in adult populations with diabetes. Our findings suggest not only that youth with diabetes are at risk for DPN but also that many already show measurable signs of DPN.

Glucose control and diabetic neuropathy: lessons from recent large clinical trials.

Diabetic peripheral and autonomic neuropathies are common complications of diabetes with broad spectrums of clinical manifestations and high morbidity. Studies using various agents to target the pathways implicated in the development and progression of diabetic neuropathy were promising in animal models. In humans, however, randomized controlled studies have failed to show efficacy on objective measures of neuropathy. The complex anatomy of the peripheral and autonomic nervous systems, the multitude of pathogenic mechanisms involved, and the lack of uniformity of neuropathy measures have likely contributed to these failures. To date, tight glycemic control is the only strategy convincingly shown to prevent or delay the development of neuropathy in patients with type 1 diabetes and to slow the progression of neuropathy in some patients with type 2 diabetes. Lessons learned about the role of glycemic control on distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy are discussed in this review.

Lipids and lipid management in diabetes.

Cardiovascular disease is more prevalent in type 1 and type 2 diabetes, and continues to be the leading cause of death among adults with diabetes. Although atherosclerotic vascular disease has a multi-factorial etiology, disorders of lipid metabolism play a central role. The coexistence of diabetes with other risk factors, in particular with dyslipidemia, further increases cardiovascular disease risk. A characteristic pattern, termed diabetic dyslipidemia, consists of increased levels of triglycerides, low levels of high density lipoprotein cholesterol, and postprandial lipemia, and is mostly seen in patients with type 2 diabetes or metabolic syndrome. This review summarizes the trends in the prevalence of lipid disorders in diabetes, advances in the mechanisms contributing to diabetic dyslipidemia, and current evidence regarding appropriate therapeutic recommendations.

Association Between Impaired Cardiovascular Autonomic Function and Hypoglycemia in Patients With Type 1 Diabetes

OBJECTIVE We studied the association between glycemic variability (GV) reflecting hypoglycemic stress and cardiovascular autonomic function in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS Forty-four type 1 diabetic patients (mean age 34 ± 13 years, 40% male, 86% Caucasian, mean diabetes duration 13 ± 6 years, mean hemoglobin A1c [HbA1c] 8.0 ± 1.2% [64 ± 5 mmol/mol]) without cardiovascular disease, dyslipidemia, or hypertension participated in this pilot study. Indices of GV reflective of hypoglycemic stress (low blood glucose index [LBGI] and area under the curve [AUC] for hypoglycemia) were computed using data obtained during 5-day continuous glucose monitoring. Cardiovascular autonomic neuropathy (CAN) was assessed using standardized cardiovascular reflex testing and measures of heart rate variability (HRV), which were analyzed as time and frequency domain measures. RESULTS Both LBGI and AUC hypoglycemia had a significant negative association with the low-frequency power of HRV (r = −0.47, P = 0.002; r = −0.43, P = 0.005, respectively) and with the high-frequency power of HRV (r = −0.37, P = 0.018; r = −0.38, P = 0.015, respectively). These inverse associations persisted after adjusting for HbA1c, although they were attenuated in multivariable analysis after adjustment for age, diabetes duration, and several other covariates. CONCLUSIONS Increased GV promoting hypoglycemic stress was associated with reduced HRV independent of glycemic control as assessed by HbA1c. These pilot data suggest that glucose variability may contribute to cardiovascular autonomic dysfunction among adults with type 1 diabetes.

Prevalence of and Risk Factors for Diabetic Peripheral Neuropathy in Youth With Type 1 and Type 2 Diabetes: SEARCH for Diabetes in Youth Study

OBJECTIVE We assessed the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) enrolled in the SEARCH for Diabetes in Youth (SEARCH) study. RESEARCH DESIGN AND METHODS The Michigan Neuropathy Screening Instrument (MNSI) was used to assess DPN in 1,734 youth with T1D (mean ± SD age 18 ± 4 years, T1D duration 7.2 ± 1.2 years, and HbA1c 9.1 ± 1.9%) and 258 youth with T2D (age 22 ± 3.5 years, T2D duration 7.9 ± 2 years, and HbA1c 9.4 ± 2.3%) who were enrolled in the SEARCH study and had ≥5 years of diabetes duration. DPN was defined as an MNSI exam score of >2. Glycemic control over time was estimated as area under the curve for HbA1c. RESULTS The prevalence of DPN was 7% in youth with T1D and 22% in youth with T2D. Risk factors for DPN in youth with T1D were older age, longer diabetes duration, smoking, increased diastolic blood pressure, obesity, increased LDL cholesterol and triglycerides, and lower HDL cholesterol (HDL-c). In youth with T2D, risk factors were older age, male sex, longer diabetes duration, smoking, and lower HDL-c. Glycemic control over time was worse among those with DPN compared with those without for youth with T1D (odds ratio 1.53 [95% CI 1.24; 1.88]) but not for youth with T2D (1.05 [0.7; 1.56]). CONCLUSIONS The high rates of DPN among youth with diabetes are a cause of concern and suggest a need for early screening and better risk factor management. Interventions in youth that address poor glycemic control and dyslipidemia may prevent or delay debilitating neuropathic complications.

Cardiovascular autonomic neuropathy associates with nephropathy lesions in American Indians with type 2 diabetes

AIMS Cardiovascular autonomic neuropathy (CAN) predicts clinical diabetic nephropathy (DN). We investigated the relationship between DN structural lesions and CAN. METHODS Sixty three Pima Indians with type 2 diabetes underwent kidney biopsies following a 6-year clinical trial testing the renoprotective efficacy of losartan vs. placebo. CAN was assessed a median 9.2years later. CAN variables included expiration/inspiration ratio (E/I), standard deviation of the normal R-R interval (sdNN), and low and high frequency signal power and their ratio (LF, HF, LF/HF); lower values reflect more severe neuropathy. Associations of CAN with renal structural variables were assessed by linear regression adjusted for age, sex, diabetes duration, blood pressure, HbA1c, glomerular filtration rate, and treatment assignment during the trial. RESULTS Global glomerular sclerosis was negatively associated with sdNN (partial r=-0.35, p=0.01) and LF (r=-0.32, p=0.02); glomerular basement membrane width was negatively associated with all measures of CAN except for LF/HF (r=-0.28 to -0.42, p<0.05); filtration surface density was positively associated with sdNN, LF, and HF (r=0.31 to 0.38, p<0.05); and cortical interstitial fractional volume was negatively associated with HF (r=-0.27, p=0.04). CONCLUSIONS CAN associates with DN lesions.

Sudomotor dysfunction as a measure of small fiber neuropathy in type 1 diabetes

BACKGROUND This study evaluated whether measuring the electrochemical skin conductance (ESC), as an indirect measure of sudomotor function, may be also a reliable surrogate for early cardiovascular autonomic neuropathy (CAN). METHODS Longitudinal study included 37 type 1 diabetes (T1D) subjects (mean age 38±13years, duration 15±7years, HbA1c 7.9±1.1%, no known complications at baseline), and 40 age-matched healthy control (HC) subjects. Mean hands ESC (ESChands) and feet (ESCfeet) were measured with the SUDOSCAN (Impeto Medical, France). CAN was assessed with heart rate variability (HRV) studies (ANSAR Inc., PA), cardiovascular autonomic reflex tests (deep-breathing, Valsalva, postural test), and positron emission tomography with sympathetic analogue [11C]meta-hydroxyephedrine. Associations between measures of CAN and ESC were estimated using Spearman correlations. Longitudinal changes were analyzed using paired t-test. RESULTS At baseline, there were no differences between T1D and HC in ESChands (69±14 vs. 69±13μS; P=0.84) or ESCfeet (82±8 vs. 78±9μS; P=0.12), while some indices of HRV and Valsalva ratio were significantly lower in T1D vs. HC. T1D subjects experienced a significant decline in both ESChands and ESCfeet at 12months (mean change -7.2±11.6µS, P=0.0006; -2.8±7.3µS, P=0.023 respectively). No significant correlations were consistently found between ESC and measures of CAN at baseline or at 12months. CONCLUSION Comparing patients with T1D to controls, no differences in ESC were observed at baseline. The associations between ESC and established measures of CAN were inconsistent, which does not support ESC as a reliable surrogate for CAN. While both hands and feet ESC declined over time, the significance of this finding is unclear and warrants further reliability testing.

Burden of Diabetic Peripheral Neuropathy in Pima Indians With Type 2 Diabetes

Diabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN) share common pathological mechanisms and are favorably impacted by intensive glycemic control. American Indians have disproportionately higher rates of type 2 diabetes (T2D), younger age of diabetes onset, and earlier development of long-term complications than other ethnic groups (1). Diabetes as an underlying cause of death is 2.5–3.5 times higher among American Indians than whites, yet the DPN burden among American Indians has not been systematically evaluated. We assessed DPN prevalence in Pima Indians and evaluated the relationship between DPN and DN. A total of 79 Pima Indians with T2D (age 53 ± 11 years, diabetes duration 25 ± 6 years, 73% female, and mean HbA1c 9.5 ± 1.9% [80 ± 7 mmol/mol]) from the Gila River community were enrolled. DPN status was ascertained using the Michigan Neuropathy Screening Instrument (MNSI) …

Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study.

OBJECTIVE Experimental studies have reported potential benefit of glucagon-like peptide-1(GLP-1) receptor agonists in preventing diabetic peripheral neuropathy (DPN). We therefore performed a proof-of-concept pilot study to evaluate the effect of exenatide, a GLP-1 agonist, on measures of DPN and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Forty-six T2D subjects (age 54±10years, diabetes duration 8±5years, HbA1c 8.2±1.3%) with mild to moderate DPN at baseline were randomized to receive either twice daily exenatide (n=22) or daily insulin glargine (n=24). The subjects, with similar HbA1c levels, were followed for 18months. The primary end point was the prevalence of confirmed clinical neuropathy (CCN). Changes in measures of CAN, other measures of small fiber neuropathy such as intra-epidermal nerve fiber density (IENFD), and quality of life were also analyzed. RESULTS Glucose control was similar in both groups during the study. There were no statistically significant treatment group differences in the prevalence of CCN, IENFD, measures of CAN, nerve conductions studies, or quality of life indices. CONCLUSIONS In this pilot study of patients with T2D and mild to moderate DPN, 18months of exenatide treatment had no significant effect on measures of neuropathy compared with glargine treatment.

Cardiovascular Autonomic Neuropathy in Adolescents and Young Adults with Type 1 and Type 2 Diabetes: The SEARCH for Diabetes in Youth Cohort Study

To estimate the prevalence of and risk factors for cardiovascular autonomic neuropathy (CAN) in adolescents and young adults with type 1 and type 2 diabetes enrolled in the SEARCH for Diabetes in Youth Study.