Cardiovascular autonomic neuropathy, erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes: findings from the DCCT/EDIC.

PURPOSE: We evaluated the association between cardiovascular autonomic neuropathy, and erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes. MATERIALS AND METHODS: Male type 1 diabetes participants (635) in the DCCT/EDIC were studied. Cardiovascular autonomic neuropathy was assessed by standardized cardiovascular reflex tests including changes in respiratory rate variation with deep breathing, Valsalva maneuver (Valsalva ratio) and changes in supine to standing diastolic blood pressure. Erectile dysfunction was assessed by a proxy item from the International Index of Erectile Function, and lower urinary tract symptoms were assessed with the AUASI (American Urological Association Symptom Index). Multivariable logistic regression models estimated the association between cardiovascular autonomic neuropathy and erectile dysfunction and/or lower urinary tract symptoms, adjusting for time weighted glycemic control, blood pressure, age and other covariates. RESULTS: Men in whom erectile dysfunction and/or lower urinary tract symptoms developed during EDIC had a significantly lower respiratory rate variation and Valsalva ratio at DCCT closeout and EDIC year 16/17 compared to those without erectile dysfunction or lower urinary tract symptoms. In adjusted analysis, participants with cardiovascular autonomic neuropathy had 2.65 greater odds of erectile dysfunction and lower urinary tract symptoms (95% CI 1.47-4.79). CONCLUSIONS: These data suggest that cardiovascular autonomic neuropathy predicts the development of urological complications in men with long-standing type 1 diabetes. Studies evaluating the mechanisms contributing to these interactions are warranted for targeting effective prevention or treatment.

Neuropathic Pain With and Without Diabetic Peripheral Neuropathy in Type 1 Diabetes.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994-2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2. RESULTS: At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-. CONCLUSIONS: NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed.

Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial.

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8-8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management.

The Use of Rescue Insulin in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: To describe rescue insulin use and associated factors in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: GRADE participants (type 2 diabetes duration <10 years, baseline A1C 6.8%-8.5% on metformin monotherapy, N = 5,047) were randomly assigned to insulin glargine U-100, glimepiride, liraglutide, or sitagliptin and followed quarterly for a mean of 5 years. Rescue insulin (glargine or aspart) was to be started within 6 weeks of A1C >7.5%, confirmed. Reasons for delaying rescue insulin were reported by staff-completed survey. RESULTS: Nearly one-half of GRADE participants (N = 2,387 [47.3%]) met the threshold for rescue insulin. Among participants assigned to glimepiride, liraglutide, or sitagliptin, rescue glargine was added by 69% (39% within 6 weeks). Rescue aspart was added by 44% of glargine-assigned participants (19% within 6 weeks) and by 30% of non-glargine-assigned participants (14% within 6 weeks). Higher A1C values were associated with adding rescue insulin. Intention to change health behaviors (diet/lifestyle, adherence to current treatment) and not wanting to take insulin were among the most common reasons reported for not adding rescue insulin within 6 weeks. CONCLUSIONS: Proportionately, rescue glargine, when required, was more often used than rescue aspart, and higher A1C values were associated with greater rescue insulin use. Wanting to use noninsulin strategies to improve glycemia was commonly reported, although multiple factors likely contributed to not using rescue insulin. These findings highlight the persistent challenge of intensifying type 2 diabetes treatment with insulin, even in a clinical trial.

The NIDDK Diabetic Foot Consortium.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetic Foot Consortium (DFC) was established in September 2018 by the NIDDK to build an organization to facilitate the highest quality of clinical research on diabetic foot ulcers (DFUs) that will answer clinically significant questions to improve DFU healing and prevent amputations. The initial focus of the DFC is to develop and validate biomarkers for DFUs that can be used in clinical care and research. The DFC consists of a data coordinating center (DCC) for operational oversight and statistical analysis, clinical sites for participant recruitment and evaluation, and biomarker analysis units (BAUs). The DFC is currently studying biomarkers to predict wound healing and recurrence and is collecting biosamples for future studies through a biorepository. The DFC plans to address the challenges of recruitment and eligibility criteria for DFU clinical trials by taking an approach of "No DFU Patient Goes Unstudied." In this platform approach, clinical history, DFU outcome, wound imaging, and biologic measurements from a large number of patients will be captured and the in-depth longitudinal data set will be analyzed to develop a computational-based DFU risk factor profile to facilitate scientifically sound clinical trial design. The DFC will expand its platform to include studies of the role of social determinants of health, such as food insecurity, housing instability, limited health literacy, and poor social support. The DFC is starting partnerships with the broad group of stakeholders in the wound care community.

Diabetic Peripheral Neuropathy and Urological Complications in Type 1 Diabetes: Findings From the Epidemiology of Diabetes Interventions and Complications Study.

OBJECTIVE: To evaluate associations between diabetic peripheral neuropathy (DPN) and urological complications in men and women with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Measurements of DPN at Epidemiology of Diabetes Intervention and Complications (EDIC) years 1, 14, and 17 and urological complications at EDIC year 17 were examined in 635 men (mean age 51.6 years, diabetes duration 29.5 years) and 371 women (mean age 50.6 years, diabetes duration 29.8 years) enrolled in the Diabetes Control and Complications Trial (DCCT)/EDIC study. DPN was defined by symptoms, signs, and abnormal electrophysiology or by abnormal Michigan Neuropathy Screening Instrument (MNSI) examination or questionnaire scores. RESULTS: Erectile dysfunction (ED) in combination with lower urinary tract symptoms (LUTS) was reported in 15% of men and female sexual dysfunction (FSD), LUTS, and urinary incontinence (UI) in 16% of women. Adjusted for age, drinking status, BMI, depression, DCCT/EDIC time-weighted mean HbA1c, microalbuminuria, hypertension, triglycerides, and statin medication use, the odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17 were 3.52 (95% CI 1.69, 7.31) times greater in men with confirmed DPN at EDIC year 13/14 compared to men without confirmed DPN. Compared to men without DPN, men with DPN based on abnormal MNSI examination or questionnaire scores had significantly higher odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17. There were no significant differences in DPN between women reporting both FSD and LUTS/UI compared with those without FSD or LUTS/UI at EDIC year 17. CONCLUSIONS: In long-standing T1D, DPN is associated with the later development of urological complications in men.

Physical Function in Middle-aged and Older Adults With Type 1 Diabetes: Long-term Follow-up of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study.

OBJECTIVE: To describe the prevalence and clinical correlates of functional limitations in middle-aged and older adults with long-standing type 1 diabetes. RESEARCH DESIGN AND METHODS: Functional limitations were assessed for 1,094 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a multicenter, longitudinal, observational follow-up of participants with type 1 diabetes randomly assigned to intensive or conventional diabetes therapy during the Diabetes Control and Complications Trial (DCCT). The primary outcome measure was a score <10 on the Short Physical Performance Battery (SPPB). The secondary outcome, self-reported functional limitation, was assessed by written questionnaire. Logistic regression models were used to assess associations of both outcomes with demographic and clinical factors (glycemic and nonglycemic factors, micro- and macrovascular complications, DCCT cohort, and treatment assignment). RESULTS: Participants were 53% male, with mean ± SD age 59.5 ± 6.8 years and diabetes duration 37.9 ± 4.9 years. The prevalence of SPPB score <10 was 21%. The prevalence of self-reported functional limitations was 48%. While DCCT treatment assignment was not associated with physical function outcomes measured ∼25 years after the end of the DCCT, the time-weighted mean DCCT/EDIC HbA1c was associated with both outcomes. Other clinical factors associated with both outcomes in multivariable analyses were BMI, general psychological distress, and cardiac autonomic neuropathy. CONCLUSIONS: Almost half of the middle-aged and older adults with long-standing type 1 diabetes reported functional limitations, which were associated with higher HbA1c and BMI, general psychological distress, and cardiac autonomic neuropathy. Future research is needed to determine whether these findings are generalizable.

On diabetic foot ulcer knowledge gaps, innovation, evaluation, prediction markers, and clinical needs.

Diabetic foot ulcers (DFUs) remain a very prevalent and challenging complication of diabetes worldwide due to high morbidity, high risks of lower extremity amputation and associated mortality. Despite major advances in diabetes treatment in general, there is a paucity of FDA approved technologies and therapies to promote successful healing. Furthermore, accurate biomarkers to identify patients at risk of non-healing and monitor response-to-therapy are significantly lacking. To date, research has been slowed by a lack of coordinated efforts among basic scientists and clinical researchers and confounded by non-standardized heterogenous collection of biospecimen and patient associated data. Novel technologies, especially those in the single and 'multiomics' arena, are being used to advance the study of diabetic foot ulcers but require pragmatic study design to ensure broad adoption following validation. These high throughput analyses offer promise to investigate potential biomarkers across wound trajectories and may support information on wound healing and pathophysiology not previously well understood. Additionally, these biomarkers may be used at the point-of-care. In combination with national scalable research efforts, which seek to address the limitations and better inform clinical practice, coordinated and integrative insights may lead to improved limb salvage rates.

The cross-sectional association of cognition with diabetic peripheral and autonomic neuropathy-The GRADE study.

BACKGROUND: Studies examining whether measures of cognition are related to the presence of diabetic peripheral neuropathy (DPN) and/or cardiovascular autonomic neuropathy (CAN) are lacking, as are data regarding factors potentially explaining such associations. METHODS: Participants were from the Glycemia Reduction Approaches in Diabetes Study (GRADE) that examined 5047 middle-aged people with type 2 diabetes of <10 years of known duration. Verbal learning and immediate and delayed recall (memory) were assessed with the Spanish English Verbal Learning Test; frontal executive function and processing speed with the Digit Symbol Substitution Test; and ability to concentrate and organize data with word and animal fluency tests. DPN was assessed with the Michigan Neuropathy Screening Instrument and CAN by indices of heart rate variability (standard deviation of normal beat to beat variation [SDNN] and root mean square of successive differences [RMSSD]). RESULTS: DPN was significantly inversely related to measures of immediate recall and processing speed. The percent of cognitive variation explained by DPN was small. Tests of CAN had an inconsistent or absent association with measures of cognition. Higher waist circumference and urine albumin creatinine (UACR) levels were the strongest correlates in the relationship between DPN and cognitive impairment. CONCLUSION: DPN, but not CAN, was cross-sectionally associated with lower performance in measures of cognition in people with type 2 diabetes of <10 years of known duration. Greater waist circumference and UACR were important variables in this association. The mechanisms underlying the cross-sectional association of DPN with cognitive impairment are unknown. Clinicaltrials.gov: NCT01794143.

Risk factors for orgasmic and concomitant erectile dysfunction in men with type 1 diabetes: a cross-sectional study.

In this study, we sought to determine the burden and characteristics of orgasmic dysfunction (OD) and concomitant erectile dysfunction (ED) in men with type 1 diabetes (T1D) enrolled in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. In 2010, we assessed orgasmic and erectile function using the International Index of Erectile Function (IIEF). Sociodemographic, clinical, and diabetes characteristics were compared by OD status (OD only, OD and ED, no ED or OD). Age-adjusted associations between risk factors and OD status were examined. OD and ED information was available from 563 men. Eighty-three men (14.7%) reported OD of whom 21 reported OD only and 62 reported OD and ED. Age-adjusted odds ratios demonstrated that men who reported OD only had higher odds of depression, low sexual desire, and decreased alcohol use compared with men reporting no dysfunction. Men with OD concomitant with ED had greater odds of elevated hemoglobin A1C, peripheral and autonomic neuropathy, and nephropathy. Men reporting both dysfunctions were also more likely to report smoking, lower urinary tract symptoms, and had greater odds of androgen deficiency than men with no sexual dysfunction. Men with longstanding T1D suffer from an increased burden of OD. Psychogenic factors predominate in men reporting OD only while men who present with concomitant ED report increased burden of diabetes severity, characteristics previously observed with incident ED. ED may be the central impediment to sexual function in men with OD and ED. Longitudinal studies to characterize OD and ED experience over time are warranted.

Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC).

BACKGROUND: The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a prospective observational follow-up of the Diabetes Control and Complications Trial (DCCT) cohort, reported persistent benefit of prior intensive therapy on retinopathy and nephropathy in type 1 diabetes mellitus. We evaluated the effects of prior intensive insulin therapy on the prevalence and incidence of cardiac autonomic neuropathy (CAN) in former DCCT intensive and conventional therapy subjects 13 to 14 years after DCCT closeout. METHODS AND RESULTS: DCCT autonomic measures (R-R variation with paced breathing, Valsalva ratio, postural blood pressure changes, and autonomic symptoms) were repeated in 1226 EDIC subjects in EDIC year 13/14. Logistic regression models were used to calculate the odds of incident CAN by DCCT treatment group after adjustment for DCCT baseline covariates, duration in the DCCT, and quantitative autonomic measures at DCCT closeout. In EDIC year 13/14, the prevalence of CAN using the DCCT composite definition was significantly lower in the former intensive group versus the former conventional group (28.9% versus 35.2%; P=0.018). Adjusted R-R variation was significantly greater in the former DCCT intensive versus the former conventional group (29.9 versus 25.9; P<0.001). Prior DCCT intensive therapy reduced the risks of incident CAN by 31% (odds ratio, 0.69; 95% confidence interval, 0.51 to 0.93) and of incident abnormal R-R variation by 30% (odds ratio, 0.70; 95% confidence interval, 0.51 to 0.96) in EDIC year 13/14. CONCLUSIONS: Although CAN prevalence increased in both groups, the incidence was significantly lower in the former intensive group compared with the former conventional group. The benefits of former intensive therapy extend to measures of CAN up to 14 years after DCCT closeout.

DCCT and EDIC studies in type 1 diabetes: lessons for diabetic neuropathy regarding metabolic memory and natural history.

The DCCT/EDIC (Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications) provides a comprehensive characterization of the natural history of diabetic neuropathy in patients with type 1 diabetes and provides insight into the impact of intensive insulin therapy in disease progression. The lessons learned about the natural history of distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy and the impact of glycemic control on neuropathy are discussed in this review.

Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, ß-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, ß-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m2, higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.

Beyond glycemic control: the effects of incretin hormones in type 2 diabetes.

The improved understanding of glucoregulatory hormones has driven the development of new pharmacologic agents to treat type 2 diabetes. One new class of antihyperglycemic medication is incretin mimetics (IMs). Incretin hormones potentiate insulin secretion following meal ingestion, a process that is impaired in patients with type 2 diabetes. GLP-1, a 30-amino acid peptide incretin hormone, is produced in the L cells of the ileum and colon. Studies have shown that a 6-week continuous GLP-1 infusion in patients with type 2 diabetes improved glycemic control and beta-cell function and delayed gastric emptying. Despite the rapid degradation and inactivation of GLP-1 by the enzyme dipeptidyl peptidase IV (DPP-IV), agents that mimic the actions of GLP-1 are of great clinical interest. First-in-class IM exenatide, a GLP-1 receptor agonist resistant to DPP-IV inactivation, mimics many beneficial glucoregulatory effects of GLP-1, such as suppressing glucagon secretion, regulating gastric emptying and satiety, and increasing glucose-dependent insulin secretion. Exenatide is an adjunctive therapy for patients who take metformin, a sulfonylurea, a thiazolidinedione, or a combination of these oral medications but have not achieved glycemic control. An 82-week, open-label extension trial has shown that exenatide is well tolerated and that the benefits, including improved glycemic control, weight loss, and mitigation of cardiovascular risk factors, are sustained.

Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion.

OBJECTIVE: To evaluate the impact of prior intensive diabetes therapy on neuropathy among former Diabetes Control and Complications Trial (DCCT) participants. RESEARCH DESIGN AND METHODS: At the conclusion of the DCCT, subjects in the intensive group were encouraged to maintain intensive therapy, and subjects in the conventional group were encouraged to begin intensive therapy. Thereafter, we annually assessed neuropathy as part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study. Neuropathy was defined using the Michigan Neuropathy Screening Instrument (MNSI). We recorded potential adverse consequences of neuropathy. RESULTS: At the first EDIC examination, 1,257 subjects participated in the neuropathy assessment. Consistent with DCCT results, the former intensive group showed a lower prevalence of neuropathy than the conventional group based on positive questionnaire (1.8 vs. 4.7%; P = 0.003) or examination (17.8 vs. 28.0%; P < 0.0001) results. Despite similar levels of glycemic control, symptoms and signs of neuropathy remained less prevalent among the former intensive group compared with the conventional group. At the beginning of the EDIC study, prior intensive therapy reduced the odds of having symptoms and signs of neuropathy using MNSI criteria by 64% (P = 0.0044) and 45% (P < 0.0001), respectively, with similar odds reductions observed for both neuropathic symptoms (51%, P < 0.0001) and neuropathic signs (43%, P < 0.0001) across 8 years of EDIC follow-up. CONCLUSIONS: The benefits of 6.5 years of intensive therapy on neuropathy status extended for at least 8 years beyond the end of the DCCT, similar to the findings described for diabetic retinopathy and nephropathy.

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.

New insights into glucose regulation.

This review article describes the regulation of glucose homeostasis in subjects with and without diabetes based on the emergence of new information and discusses modes of action, attributes, and limitations of current diabetes therapies. In normal physiology, glucose homeostasis is tightly controlled by the interaction of pancreatic and gut hormones. Since the 1920s, diabetes has been viewed as a disease caused by deficient secretion of insulin, resulting in reduced glucose uptake and subsequent hyperglycemia. The discovery in the 1950s of the pancreatic hormone glucagon, which opposes insulin by increasing glucose appearance in the circulation, resulted in a bihormonal model of glucose homeostasis. More recently, with the discovery of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) in the 1970s and the pancreatic hormone amylin in the 1980s, it is now understood that several organs and hormones play roles in maintaining glucose homeostasis. Therapies for diabetes have focused on compensation for deficient insulin action through stimulation of insulin secretion, administration of insulin itself, reduction of peripheral insulin resistance, or decreased glucose absorption from the intestine. The discoveries of amylin and GLP-1 have furthered our understanding of the abnormalities involved in diabetes, enabling the development of additional therapeutic options.

A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes.

OBJECTIVE: To compare the efficacy and safety of continuous subcutaneous insulin infusion (CSII) and multiple daily injection (MDI) in older adults with insulin-treated type 2 diabetes and to assess treatment satisfaction and quality of life. RESEARCH DESIGN AND METHODS: Adults (n = 107) > or =60 years of age (mean age 66 years) with insulin-treated type 2 diabetes (mean duration 16 years, BMI 32 kg/m(2), and HbA(1C) [A1C] 8.2%) were randomized to CSII (using insulin lispro) or MDI (using insulin lispro and insulin glargine) in a two-center, 12-month, prospective, randomized, controlled clinical trial. Efficacy was assessed with A1C, safety by frequency of hypoglycemia, and treatment satisfaction and quality of life with the Diabetes Quality of Life Clinical Trial Questionnaire and the 36-item short-form health survey, version 2. RESULTS: Forty-eight CSII subjects (91%) and 50 MDI subjects (93%) completed the study. Mean A1C fell by 1.7 +/- 1.0% in the CSII group to 6.6% and by 1.6 +/- 1.2% in the MDI group to 6.4%. The difference in A1C between treatment groups was not statistically significant (P = 0.20). Eighty-one percent of CSII subjects and 90% of MDI subjects experienced at least one episode of minor (self-treated) hypoglycemia (P = 0.17), and three CSII and six MDI subjects experienced severe hypoglycemia (P = 0.49). Rates of severe hypoglycemia were similarly low in the two groups (CSII 0.08 and MDI 0.23 events per person-year, P = 0.61). Weight gain did not differ between groups (P = 0.70). Treatment satisfaction improved significantly with both CSII and MDI (P < 0.0001), and the difference between groups was not statistically significant (P = 0.58). CONCLUSIONS: In older subjects with insulin-treated type 2 diabetes, both CSII and MDI achieved excellent glycemic control with good safety and patient satisfaction.

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.

Cardiovascular Autonomic Neuropathy, Sexual Dysfunction, and Urinary Incontinence in Women With Type 1 Diabetes.

OBJECTIVE: This study evaluated associations among cardiovascular autonomic neuropathy (CAN), female sexual dysfunction (FSD), and urinary incontinence (UI) in women with type I diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: We studied 580 women with T1DM in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC). CAN was defined as: 1) R-R variation <15 with deep breathing or 2) R-R variation of 15-19.9 plus Valsalva ratio ≤1.5 or a supine-to-standing drop of 10 mmHg in diastolic blood pressure. A Sandvik Severity Index of 3-12 defined UI, and a Female Sexual Function Index (FSFI-R) score ≥22.75 defined FSD. Multivariable models estimated associations among CAN, FSD, and UI. RESULTS: At EDIC year 17, FSD was observed in 41% of women and UI in 30%. No statistically significant associations were observed between measures of CAN at DCCT closeout and subsequent report of FSD or UI. At EDIC year 16/17, there was a 53% increased odds of having UI with a Valsalva ratio ≤1.5. At both EDIC year 13/14 and EDIC year 16/17, a 5-unit increase in R-R variation was associated with a 1.11 greater odds of having FSD. CONCLUSIONS: In women with T1DM in the DCCT/EDIC, we found significant increased odds of FSD and UI with specific measures of CAN. In long-standing T1DM, CAN may predict development of FSD and may be a useful surrogate for generalized diabetic autonomic neuropathy.