James L. Rosenzweig

Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society

OBJECTIVE To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTS Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. EVIDENCE The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESS Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association’s Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society’s Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONS The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

Primary Prevention of Cardiovascular Disease and Type 2 Diabetes in Patients at Metabolic Risk: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The objective was to develop clinical practice guidelines for the primary prevention of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) in patients at metabolic risk. CONCLUSIONS Healthcare providers should incorporate into their practice concrete measures to reduce the risk of developing CVD and T2DM. These include the regular screening and identification of patients at metabolic risk (at higher risk for both CVD and T2DM) with measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose. All patients identified as having metabolic risk should undergo 10-yr global risk assessment for either CVD or coronary heart disease. This scoring will determine the targets of therapy for reduction of apolipoprotein B-containing lipoproteins. Careful attention should be given to the treatment of elevated blood pressure to the targets outlined in this guideline. The prothrombotic state associated with metabolic risk should be treated with lifestyle modification measures and in appropriate individuals with low-dose aspirin prophylaxis. Patients with prediabetes (impaired glucose tolerance or impaired fasting glucose) should be screened at 1- to 2-yr intervals for the development of diabetes with either measurement of fasting plasma glucose or a 2-h oral glucose tolerance test. For the prevention of CVD and T2DM, we recommend that priority be given to lifestyle management. This includes antiatherogenic dietary modification, a program of increased physical activity, and weight reduction. Efforts to promote lifestyle modification should be considered an important component of the medical management of patients to reduce the risk of both CVD and T2DM.

Protein Kinase C-β Contributes to Impaired Endothelial Insulin Signaling in Humans With Diabetes Mellitus

Background— Abnormal endothelial function promotes atherosclerotic vascular disease in diabetes. Experimental studies indicate that disruption of endothelial insulin signaling, through the activity of protein kinase C-&bgr; (PKC&bgr;) and nuclear factor &kgr;B, reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus. Methods and Results— We measured protein expression and insulin response in freshly isolated endothelial cells from patients with type 2 diabetes mellitus (n=40) and nondiabetic controls (n=36). Unexpectedly, we observed 1.7-fold higher basal endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 in patients with diabetes mellitus (P=0.007) without a difference in total eNOS expression. Insulin stimulation increased eNOS phosphorylation in nondiabetic subjects but not in diabetic patients (P=0.003), consistent with endothelial insulin resistance. Nitrotyrosine levels were higher in diabetic patients, indicating endothelial oxidative stress. PKC&bgr; expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=−0.541, P=0.02). Inhibition of PKC&bgr; with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes mellitus. Endothelial nuclear factor &kgr;B activation was higher in diabetes mellitus and was reduced with PKC&bgr; inhibition. Conclusions— We provide evidence for the presence of altered eNOS activation, reduced insulin action, and inflammatory activation in the endothelium of patients with diabetes mellitus. Our findings implicate PKC&bgr; activity in endothelial insulin resistance.

Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society.

OBJECTIVE To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTS Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. EVIDENCE The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESS Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Associations Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Societys Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONS The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

The economic consequences of diabetes and cardiovascular disease in the United States

Diabetes-related care and complications constitute a significant proportion of the United States’ (US) health care expenditure. Of these complications, cardiovascular disease (CVD) is a major component. Higher morbidity and mortality rates translate to higher costs of care in patients with diabetes compared to those who do not have the disease. Minorities bear a disproportionate burden of diabetes and CVD. We review this disparity and examine potential etiologies for it in Hispanics and African-Americans, the two largest minority groups in the US. We examine strategies in these populations that may improve outcomes in diabetes and CVD, potentially decreasing health care costs.

Depressive Symptoms, Antidepressant Use, and the Incidence of Diabetes in the Black Women’s Health Study

OBJECTIVE To assess the relationship of depressive symptoms and use of antidepressants with incident type 2 diabetes in prospective data from a large cohort of U.S. African American women. RESEARCH DESIGN AND METHODS The Black Women’s Health Study (BWHS) is an ongoing prospective cohort study. We followed 35,898 women from 1999 through 2011 who were without a diagnosis of diabetes and who had completed the Center for Epidemiologic Studies Depression Scale (CES-D) in 1999. CES-D scores were categorized as <16, 16–22, 23–32, and ≥33, which reflected increasingly more depressive symptoms. We estimated incidence rate ratios (IRRs) and 95% CIs for incident diabetes using Cox proportional hazards models. The basic multivariable model included age, time period, family history of diabetes, and education. In further models, we controlled for lifestyle factors and BMI. We also assessed the association of antidepressant use with incident diabetes. RESULTS Over 12 years of follow-up, there were 3,372 incident diabetes cases. Relative to CES-D score <16, IRRs (95% CI) of diabetes for CES-D scores 16–22, 23–32, and ≥33 were 1.23 (1.12–1.35), 1.26 (1.12–1.41), and 1.45 (1.24–1.69), respectively, in the basic multivariate model. Multiple adjustment for lifestyle factors and BMI attenuated the IRRs to 1.11 (1.01–1.22), 1.08 (0.96–1.22), and 1.22 (1.04–1.43). The adjusted IRR for antidepressant use was 1.26 (1.11–1.43). Results were similar among obese women. CONCLUSIONS Both depressive symptoms and antidepressant use are associated with incident diabetes among African American women. These associations are mediated in part, but not entirely, through lifestyle factors and BMI.

Birth Weight and Risk of Type 2 Diabetes in the Black Women’s Health Study: Does Adult BMI Play a Mediating Role?

OBJECTIVE To assess the association of birth weight with incident type 2 diabetes, and the possible mediating influence of obesity, in a large cohort of U.S. black women. RESEARCH DESIGN AND METHODS The Black Women’s Health Study is an ongoing prospective study. We used Cox proportional hazards models to estimate incidence rate ratios (IRRs) and 95% CI for categories of birth weight (very low birth weight [<1,500 g], low birth weight [1,500–2,499 g], and high birth weight [≥4,000 g]) in reference to normal birth weight (2,500–3,999 g). Models were adjusted for age, questionnaire cycle, family history of diabetes, caloric intake, preterm birth, physical activity, years of education, and neighborhood socioeconomic status with and without inclusion of terms for adult BMI. RESULTS We followed 21,624 women over 16 years of follow-up. There were 2,388 cases of incident diabetes. Women with very low birth weight had a 40% higher risk of disease (IRR 1.40 [95% CI 1.08–1.82]) than women with normal birth weight; women with low birth weight had a 13% higher risk (IRR 1.13 [95% CI 1.02–1.25]). Adjustment for BMI did not appreciably change the estimates. CONCLUSIONS Very low birth weight and low birth weight appear to be associated with increased risk of type 2 diabetes in African American women, and the association does not seem to be mediated through BMI. The prevalence of low birth weight is especially high in African American populations, and this may explain in part the higher occurrence of type 2 diabetes.

Positive Association between Plasma Amylin and Cognition in a Homebound Elderly Population

Our recent study reported that amylin, a pancreatic peptide that readily crosses the blood-brain barrier, improves learning and memory in Alzheimers disease mouse models. However, the relationship between peripheral amylin and cognition in humans is unknown. In this follow-up study, using a cross-sectional, homebound elderly population, improvement in cognitive function with increasing quartiles of plasma amylin was suggested by positive association with verbal memory (p = 0.0002) and visuoconstruction tasks (p = 0.004), and inverse association with timed measures of attention (p < 0.0001) and executive function (p = 0.04). After adjusting for demographic information, apolipoprotein E4 allele, diabetes, stroke, kidney function, and lipid profile, log10 of plasma amylin remained associated with these cognitive domains. In contrast, plasma amyloid-β peptide was not associated with these specific cognitive domains. Our study suggests that peripheral amylin may be protective for cognitive decline, especially in the domains affected by Alzheimers disease.

Comparison of diabetes control among Haitians, African Americans, and non-Hispanic whites in an urban safety-net hospital

OBJECTIVE To compare diabetes care and outcomes among Haitians, African Americans, and non-Hispanic whites. RESEARCH DESIGN AND METHODS We analyzed data from 715 Haitian, 1,472 African American, and 466 non-Hispanic white adults with diabetes using χ2 testing and multiple logistic regression. RESULTS Haitians had a higher mean A1C than African Americans (8.2 ± 1.9 vs. 7.7 ± 2.0%) and non-Hispanic whites (7.5 ± 1.7%) (both P < 0.0001). There was no difference in completion of process measures. Haitians were more likely than non-Hispanic whites to have elevated LDL cholesterol or blood pressure. Macrovascular complications were fewer among Haitians than African Americans (adjusted odds ratio 0.35 [95% CI 0.23–0.55]), as were microvascular complications (0.56 [0.41–0.76]). Haitians also had fewer macrovascular (0.32 [0.20–0.50]) and microvascular (0.55 [0.39–0.79]) complications than non-Hispanic whites. CONCLUSIONS Haitians have worse glycemic control than African Americans or non-Hispanic whites. Future research and interventions to improve diabetes care should target Haitians as a distinct racial/ethnic group.

Plasma Amylin and Cognition in Diabetes in the Absence and the Presence of Insulin Treatment

Background Plasma amylin is positively associated with cognitive function in humans. Amylin treatment improves memory in Alzheimer’s mouse models. However, the relationship between plasma amylin, diabetes and cognition is not clear. Objectives In this study we examined the concentration of plasma amylin, its relationship with diabetes and cognition. Material and Method A cross-sectional, homebound elderly population with data of plasma amylin under fasting condition and cognitive measurements was used. Results We found that subjects with a long and chronic duration of diabetes were more likely to take insulin treatment and have reduced secretion of amylin. Compared to non-diabetics, diabetic subjects without insulin treatment had a higher concentration, but those with insulin treatment had a lower concentration, of plasma amylin [median (Q1, Q3): 20 (11.0, 36.2) vs. 25.2 (13.2, 50.6) vs. 15.0 (4.9, 33.8), p<0.0001]. In the whole sample vs. in the absence of diabetes, plasma amylin was positively associated with logical memory delayed recall (β= +0.61, SE=0.25, p=0.02 vs. β=+0.80, SE=0.33, p=0.02) and block design (β=+0.62, SE=0.24, p=0.009 vs. β=+0.93, SE=0.31, p=0.003), and negatively associated with Trailmaking A scores (β= −6.21, SE=1.55, p<0.0001 vs. β=−7.51, SE=1.95, p=0.0001) and Trailmaking B (β= −4.32, SE=2.13, p=0.04 vs. β= −5.86, SE=2.73, p=0.04). All these relationships disappeared in the presence of diabetes regardless the treatment. Conclusion This study suggests that secretion of amylin by pancreas compensates and then deteriorates depending on the duration of diabetes. Amylin’s activities for cognition are impaired in the presence of diabetes.