Longitudinal Effects of Glucose-Lowering Medications on ß-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and ß-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting ß-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test ß-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of ß-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of ß-cell function, the nature of the change in ß-cell responses reflected those in ß-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and ß-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of ß-cell function in the progression of type 2 diabetes.

Beta-cell function in type 2 diabetes (T2DM): Can it be preserved or enhanced?

Type 2 diabetes (T2DM) is a complex metabolic disorder manifested by hyperglycemia, insulin resistance, and deteriorating beta-cell function. A way to prevent progression of the disease might be to enhance beta-cell function and insulin secretion. However, most previous studies examined beta-cell function while patients were using glycemia-lowering agents without an adequate period off medications (washout). In the present review we focus on studies with a washout period. We performed a literature search (2010 to June 2021) using beta-cell function and enhancement. The evidence shows that beta-cell function can be enhanced. Bariatric surgery and very low calorie diets show improvement in beta-cell function in many individuals. In addition, use of glucagon-like peptide-1 receptor agonists for prolonged periods (3 years or more) can also lead to improvement of beta-cell function. Further research is needed to understand the mechanisms leading to improved beta-cell function and identify agents that could enhance beta-cell function in patients with T2DM.

Management of diabetes in elderly patients during the COVID-19 pandemic: current and future perspectives.

Introduction: The COVID-19 pandemic has affected the entire population with the most deleterious effects in elders. Elders, especially those with diabetes, are at the highest risk of COVID-19 related adverse outcomes and mortality. This is usually linked to the comorbidities that accumulate with age, diabetes-related chronic inflammation, and the pandemic's psychosocial effects.Areas covered: We present some approaches to manage these complicated elderly patients with diabetes during the COVID-19 pandemic. In the inpatient setting, we suggest similar (pre-pandemic) glycemic targets and emphasize the importance of using IV insulin and possible use of continuous glucose monitoring to reduce exposure and PPE utilization. Outside the hospital, we recommend optimal glycemic control within the limits imposed by considerations of safety. We also describe the advantages and challenges of using various technological platforms in clinical care.Expert opinion: The COVID-19 pandemic has lifted the veil off serious deficiencies in the infrastructures for care at both the individual level and the population level and also highlighted some of the strengths, all of which affect individuals with diabetes and COVID-19. We anticipate that things will not return to 'normal' after the COVID-19 pandemic has run its course, but rather they will be superseded by 'New Normal.'

The assessment and management of quality of life of older adults with diabetes mellitus.

Introduction: As the population ages, the number of older adults with diabetes mellitus will continue to rise. The burden of diabetes on older adults is significant due to the disease itself, its complications, and its treatments. This is compounded by geriatric syndromes such as frailty and cognitive dysfunction. Consequently, health and diabetes-related quality of life (QoL) are diminished.Areas covered: This article reviews the value of assessing QoL in providing patient-centered care and the associations between QoL measures and health outcomes. The determinants of QoL particular to diabetes and the older population are reviewed, including psychosocial, physical, and cognitive burdens of diabetes and aging and the impact of hypoglycemia on QoL. Strategies are described to alleviate these burdens and improve QoL, and barriers to multidisciplinary patient-centered care are discussed. QoL measurement instruments are reviewed.Expert opinion: The goals of treating diabetes and its complications should be considered carefully along with each patient's capacity to withstand the burdens of treatment. This capacity is reduced by socioeconomic, psychological, cognitive, and physical factors reduces this capacity. Incorporating measurement of HRQoL into clinical practices is possible, but deficiencies in the systems of health-care delivery need to be addressed to facilitate their use.

Absent or diminished pedal pulses and estimated GFR decline in patients with diabetic kidney disease.

Background: Peripheral artery disease (PAD) is a complication of type 2 diabetes that leads to critical limb ischemia and amputation. We tested whether absent or diminished pedal pulses (ADPPs) predicts subsequent renal functional decline in patients with diabetic chronic kidney disease (CKD). We also examined the association between urinary biomarkers and ADPP as well as worsening CKD. Methods: Using a prospective longitudinal design, we studied 91 patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) from 7 to 146 mL/min/1.73 m2. Baseline pedal pulses were assessed by standardized history and physical examination. The primary endpoint was decline in eGFR >30%. Potential confounders of the relationship between pedal pulses and eGFR were assessed by multivariable logistic regression. Results: Of 91 participants (median age 58 (range 30-83); median eGFR 72.4 ± 33.4 mL/min/1.73 m2), 43% had at least one ADPP. Baseline ADPP associated with increased risk of greater than 30% decline in eGFR (OR= 3.67, p = .004). This association remained significant (OR = 3.09, p = .029) after adjustment for traditional risk factors of renal function decline in diabetic kidney disease (DKD). In addition, urinary endothelin-1 (ET-1) was higher among patients with ADPP (p =.0006) and associated with eGFR decline greater than 30% (adjusted OR = 1.81, p = .035). Conclusions: ADPP is a strong predictor of decline in renal function in type 2 diabetes. Patients with type 2 diabetes and abnormal pedal pulses should be screened for DKD and monitored closely for progression of CKD.

Measurements of serum DHEA and DHEA sulphate levels improve the accuracy of the low-dose cosyntropin test in the diagnosis of central adrenal insufficiency.

BACKGROUND AND OBJECTIVES: The diagnosis of central adrenal insufficiency (AI) continues to be challenging, especially when it is partial. We have recently demonstrated the value of measuring serum dehydroepiandrosterone sulfate (DHEA-S) in establishing the diagnosis of central AI. The current investigation examined the added value of measuring serum dehydroepiandrosterone (DHEA) levels during low-dose (1 µg) cosyntropin (LDC) stimulation in patients suspected to have central AI. METHODS: Baseline and LDC-stimulated cortisol, DHEA, and DHEA-S were measured preoperatively in 155 consecutive patients with pituitary masses and 63 healthy subjects. Hypothalamic-pituitary adrenal (HPA) function was normal (NL-HPA) in 97 of the patients and was impaired (impaired HPA) in 58 patients. Patients with NL-HPA underwent surgical removal of the sellar masses and received no glucocorticoids before, during, or after surgery. RESULTS: Baseline and LDC-stimulated serum cortisol, DHEA, and DHEA-S in patients with NL-HPA were similar to those of normal subjects. In contrast, patients with impaired HPA had lower baseline and LDC-stimulated serum cortisol, DHEA, and DHEA-S levels. There were 18 subjects in the latter group whose LDC-stimulated serum cortisol levels were greater than 18.0 µg/dl. In those 18 subjects, baseline and LDC-stimulated DHEA and DHEA-S levels were similar to the whole group of patients with impaired HPA function. The molar ratio of cortisol to DHEA did not change with LDC stimulation in normal subjects and those with NL-HPA. In contrast, patients with impaired HPA had a higher baseline cortisol to DHEA molar ratio that increased further with LDC stimulation. CONCLUSIONS: Patients with impaired HPA function have a more severe loss in DHEA secretion than that of glucocorticoids. Measurements of serum DHEA levels during LDC simulation provide additional valuable information that improves the diagnostic accuracy of LDC in patients suspected to have central AI. We recommend the inclusion of DHEA and DHEA-S measurements in the laboratory assessment of HPA function.