Continuous Glucose Monitoring for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes.

Context: Patients with long-standing type 1 diabetes (T1D) are at increased risk for severe hypoglycemia because of defects in glucose counterregulation and recognition of hypoglycemia symptoms, in part mediated through exposure to hypoglycemia. Objective: To determine whether implementation of real-time continuous glucose monitoring (CGM) as a strategy for hypoglycemia avoidance could improve glucose counterregulation in patients with long-standing T1D and hypoglycemia unawareness. Design, Setting, Participants, and Intervention: Eleven patients with T1D disease duration of ∼31 years were studied longitudinally in the Clinical & Translational Research Center of the University of Pennsylvania before and 6 and 18 months after initiation of CGM and were compared with 12 nondiabetic control participants. Main Outcome Measure: Endogenous glucose production response derived from paired hyperinsulinemic stepped-hypoglycemic and euglycemic clamps with infusion of 6,6-2H2-glucose. Results: In patients with T1D, hypoglycemia awareness (Clarke score) and severity (HYPO score and severe events) improved (P < 0.01 for all) without change in hemoglobin A1c (baseline, 7.2% ± 0.2%). In response to insulin-induced hypoglycemia, endogenous glucose production did not change from before to 6 months (0.42 ± 0.08 vs 0.54 ± 0.07 mg·kg-1·min-1) but improved after 18 months (0.84 ± 0.15 mg·kg-1·min-1; P < 0.05 vs before CGM), albeit remaining less than in controls (1.39 ± 0.11 mg·kg-1·min-1; P ≤ 0.01 vs all). Conclusions: Real-time CGM can improve awareness and reduce the burden of problematic hypoglycemia in patients with long-standing T1D, but with only modest improvement in the endogenous glucose production response that is required to prevent or correct low blood glucose.

An Adult Health Care-Based Pediatric to Adult Transition Program for Emerging Adults With Type 1 Diabetes.

Purpose The purpose of the study was to evaluate an adult health care program model for emerging adults with type 1 diabetes transitioning from pediatric to adult care. Methods Evaluation of the Pediatric to Adult Diabetes Transition Clinic at the University of Pennsylvania included a cohort of 72 emerging adults with type 1 diabetes, ages 18 to 25 years. Data were extracted from transfer summaries and the electronic medical record, including sociodemographic, clinical, and follow-up characteristics. Pre- and postprogram assessment at 6 months included mean daily blood glucose monitoring frequency (BGMF) and glycemic control (A1C). Paired t tests were used to examine change in outcomes from baseline to 6 months, and multiple linear regression was utilized to adjust outcomes for baseline A1C or BGMF, sex, diabetes duration, race, and insulin regimen. Open-ended survey responses were used to assess acceptability amongst participants. Results From baseline to 6 months, mean A1C decreased by 0.7% (8 mmol/mol), and BGMF increased by 1 check per day. Eighty-eight percent of participants attended ≥2 visits in 6 months, and the program was rated highly by participants and providers (pediatric and adult). Conclusions This study highlights the promise of an adult health care program model for pediatric to adult diabetes transition.

Perspectives on care for young adults with type 1 diabetes transitioning from pediatric to adult health systems: A national survey of pediatric endocrinologists.

BACKGROUND: Healthcare transition from pediatric to adult care for young adults (YA) with type 1 diabetes (T1D) is associated with risk of adverse outcomes. Consensus recommendations exist from US professional societies on transition care for YA with T1D, but it is not known whether they have been widely adopted. We describe experiences, barriers, and provider characteristics associated with transition care in a national sample of pediatric endocrinologists. METHODS: US pediatric endocrinologists identified through the American Medical Association Physician Masterfile were sent an electronic survey. RESULTS: Response rate was 16% (164/1020) representing 32 states. The majority of pediatric endocrinologists (age 44 ± 10; years in practice 12 ± 11) were female (67%) and worked in academic centers (75%). Main reasons for transfer were age (49%) and glycemic control (18%). Barriers to transition included ending long-therapeutic relationships with patients (74%), lack of transition protocols (46%), and perceived deficiencies in adult care (42%). The majority of pediatric endocrinologists reported lack of transition training (68%); those who received training were less likely to have difficulty ending patient relationships [odds ratio (OR) = 0.39, P = .03], more likely to perform patient record transfer to adult systems (OR=1.27, P = .006), and less likely to report patient returns to pediatric care after transfer (OR=0.49, P = .01), independent of endocrinologist gender, years in practice, or practice type. CONCLUSIONS: There is wide variation in transition care for YA with T1D among US pediatric endocrinologists despite consensus recommendations. Dissemination of educational programming on transition care and provision of actionable solutions to overcome local health system and perceived barriers is needed.

Challenges in recruiting subjects to a pilot trial of patient-managed in-hospital insulin.

BACKGROUND: To examine the feasibility of implementing clinician-supported inpatient self-managed insulin to aid in the planning of a randomized clinical trial. RESULTS: We conducted a proof-of-concept interventional study of inpatients with diabetes mellitus who had hospital orders for basal-bolus or sliding scale insulin. Patients meeting inclusion criteria were offered the opportunity to manage their own basal-bolus insulin with support from a diabetes nurse practitioner. Over a three-month screening period, we conducted 361 screens in 336 patients, only eleven of whom met all inclusion criteria. None of these eleven eligible patients elected to enroll. The most common reason for refusal was lack of interest in self-managing insulin while acutely ill (36 %). DISCUSSION: Future studies of patient-managed in-hospital insulin should consider enrolling less acutely ill patients with longer anticipated lengths of stay. TRIALS REGISTRATION: NCT02144441.

Effect of exenatide, sitagliptin, or glimepiride on ß-cell secretory capacity in early type 2 diabetes.

OBJECTIVE: Agents that augment GLP-1 effects enhance glucose-dependent ß-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on ß-cell secretory capacity, an in vivo measure of functional ß-cell mass, early in the course of T2D. RESEARCH DESIGN AND METHODS: We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIRarg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIRpot]), and 340 mg/dL (maximum arginine-induced insulin release [AIRmax]) hyperglycemic clamp conditions, in which AIRmax provides the ß-cell secretory capacity. RESULTS: The change in AIRpot was significantly greater with glimepiride versus exenatide treatment (P < 0.05), and a similar trend was notable for the change in AIRmax (P = 0.1). Within each group, the primary outcome measure, AIRmax, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P < 0.05). α-Cell glucagon secretion (AGRmin) was also increased with glimepiride treatment (P < 0.05), and the change in AGRmin trended higher with glimepiride than with exenatide (P = 0.06). CONCLUSIONS: After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional ß-cell mass as measured by ß-cell secretory capacity, whereas glimepiride appeared to enhance ß- and α-cell secretion.

Severe insulin resistance and hypertriglyceridemia after childhood total body irradiation.

OBJECTIVE: To characterize the metabolic phenotype of 2 cases of normal weight young women who developed type 2 diabetes (T2D), severe insulin resistance (insulin requirement >200 units/day), marked hypertriglyceridemia (>2000 mg/dL), and hepatic steatosis beginning 9 years after undergoing total body irradiation (TBI) and bone marrow transplantation for childhood cancer. METHODS: Fasting plasma glucose, insulin, free fatty acids (FFAs), leptin, adiponectin, resistin, TNFα, and IL-6 were measured in each case and in 8 healthy women; Case 1 was also assessed after initiating pioglitazone. Coding regions and splice junctions of PPARG, LMNA, and AKT2 were sequenced in Case 1 and of PPARG in Case 2 to evaluate for familial partial lipodystrophies. Genotyping of APOE was performed in Case 1 to rule out type III hyperlipoproteinemia. RESULTS: Both cases had elevated plasma levels of insulin, leptin, resistin, and IL-6, high-normal to elevated TNFα, and low to low-normal adiponectin in keeping with post-receptor insulin resistance and adipose tissue inflammation. Case 1 experienced a biochemical response to pioglitazone. No causative mutations for partial lipodystrophies or type III hyperlipoproteinemia were identified. CONCLUSION: Though metabolic derangements have previously been reported in association with TBI, few cases have described insulin resistance and hypertriglyceridemia as severe as that seen in our patients. We speculate that early childhood TBI may impede adipose tissue development leading to metabolic complications from an attenuated ability of adipose tissue to accommodate caloric excess, and propose that this extreme metabolic syndrome be evaluated for as a late complication of TBI.

Type 2 diabetes does not attenuate racial differences in coronary calcification.

AIMS: Coronary artery calcification (CAC) is a strong predictor of atherosclerotic cardiovascular disease (CVD). Whites appear to have a higher prevalence of CAC than African-Americans (AAs), but it is unknown if type 2 diabetes, a major cardiovascular risk factor, attenuates this difference. We investigated the relationship of race and CAC in a sample of patients with type 2 diabetes without clinical CVD. METHODS: multivariable analyses of self-reported ethnicity and CAC scores, stratified by gender, in 861 subjects [32% AA, 66.9% male] with type 2 diabetes. RESULTS: AA race was associated with lower CAC scores in age-adjusted models in males [Tobit ratio for AAs vs. Whites 0.14 (95% CI 0.08-0.24, p<0.001)] and females [Tobit ratio 0.26 (95% CI 0.09-0.77, p=0.015)]. This persisted in men after adjustment for traditional, metabolic and inflammatory risk factors, but adjustment for plasma triglycerides [0.48 (95% CI 0.15-1.49, p=0.201)] and HOMA-IR [0.28 (95% CI 0.08-1.03, p=0.055)] partially attenuated the association in women. CONCLUSIONS: relative to African-Americans, White race is a strong predictor of CAC, even in the presence of type 2 diabetes. The relationship in women appears less robust possibly due to gender differences in metabolic risk factors.

Insulin sensitivity, food intake, and cravings with premenstrual syndrome: a pilot study.

OBJECTIVE: The objective of this pilot study was to evaluate possible differences in insulin sensitivity, food intake, and cravings between the follicular and luteal phases of the menstrual cycle in women with premenstrual syndrome (PMS). METHODS: Subjects were screened for PMS using the Penn Daily Symptom Rating (DSR) scale. Each subject had two overnight admissions (once in each cycle phase) to the Hospital of the University of Pennsylvania. They performed 3-day diet histories prior to each hospitalization. After admission, subjects received dinner and a snack, then were fasted until morning, when they underwent a frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity was determined by Minimal Model analysis. Blinded analysis of diet histories and inpatient food intake was performed by a registered dietitian. RESULTS: There was no difference found in insulin sensitivity between cycle phases (n = 7). There were also no differences in proportions of macronutrients or total kilocalories by cycle phase, despite a marked difference in food cravings between cycle phase, with increased food cravings noted in the luteal phase (p = 0.002). Total DSR symptom scores decreased from a mean of 186 (+/-29.0) in the luteal phase to 16.6 (+/-14.2) in the follicular phase. Women in this study consumed relatively high proportions of carbohydrates (55%-64%) in both cycle phases measured. CONCLUSIONS: These findings reinforce the suggestion that although the symptom complaints of PMS are primarily confined to the luteal phase, the neuroendocrine background for this disorder may be consistent across menstrual cycle phases.

Diabetes and hypertension: epidemiology of the relationship and pathophysiology of factors associated with these comorbid conditions.

Diabetes and hypertension frequently coexist, leading to additive increases in the risk of life-threatening cardiovascular events. Hypertension is a common comorbid condition in patients with type 1 or type 2 diabetes when compared with the general population and occurs in 75% of patients with the more prevalent form of diabetes, type 2. Arterial blood pressure plays an important role in the development of renal damage and presents a complex relationship. It is well-known that hypertension accelerates the course of microvascular and macrovascular complications of diabetes and that hypertension often precedes type 2 diabetes and vice versa. Patients with type 1 and 2 diabetes and nephropathy frequently have circadian changes in blood pressure that correlate to nephropathy risk. Early detection of nocturnal hypertension and early intervention with angiotensin blockade may delay progression of diabetic nephropathy.

Menstrual cycle effects on insulin sensitivity in women with type 1 diabetes: a pilot study.

BACKGROUND: Many women complain of difficulty maintaining euglycemia during the luteal phase of the menstrual cycle. This pilot study's objective was to evaluate possible differences in insulin sensitivity between follicular and luteal phases in women with type 1 diabetes. METHODS: Women using insulin infusion pumps (n = 5, mean age 29.2 +/- 10.9 years, mean body mass index 24 +/- 1.8 kg/m(2)) underwent frequently sampled intravenous glucose tolerance tests during each cycle phase. Insulin sensitivity and glucose effectiveness were determined by Minimal Model analysis. RESULTS: Non-insulin-mediated glucose disposal increased during the luteal phase (0.009 +/- 0.004 min(1)) versus the follicular phase (0.005 +/- 0.003 min(1)) (P < 0.05). Although no significant differences were found in mean insulin sensitivity between follicular (0.76 +/- 0.27 x 10(4)/min(1) /microU/mL) and luteal phase (0.58 +/- 0.26 x 10(4)/min(1) /microU/ mL), three of the five subjects had a decline in insulin sensitivity. CONCLUSIONS: Elevated blood glucose during the luteal phase may increase insulin-independent glucose disposal. Some individuals appear more responsive to menstrual cycle effects on insulin sensitivity. Women should be encouraged to use available self-monitoring technology to identify possible cyclical variations in blood glucose that might require clinician review and insulin dosage adjustments.

Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients.

CONTEXT: In patients with type 1 diabetes and reduced awareness of hypoglycemia, the glycemic thresholds for activation of counterregulatory hormone and symptom responses to hypoglycemia are impaired, in part due to recurrent episodes of hypoglycemia. Islet transplantation can ameliorate occurrences of hypoglycemia in these patients. OBJECTIVE: The objective of the study was to determine whether the avoidance of hypoglycemia achieved through islet transplantation results in improved glycemic thresholds for counterregulatory responses. SETTING: The study was conducted at a general clinical research center. PARTICIPANTS: Seven islet transplant recipients, six type 1 diabetic, and eight nondiabetic control subjects participated in the study. INTERVENTION: We performed a stepped hyperinsulinemic hypoglycemic clamp and, in 12 subjects, a paired hyperinsulinemic euglycemic clamp to calculate the glycemic thresholds for and magnitude of counterregulatory responses. RESULTS: The glycemic thresholds for all counterregulatory hormone and symptom responses in the islet transplant group were comparable with normal and higher than in the type 1 diabetes group (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of the glucagon and epinephrine responses in the islet transplant group, although greater than in the type 1 diabetes group (P < 0.05 for both), remained less than normal (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of GH secretion in the islet transplant group was comparable with normal and greater than in the type 1 diabetes group (P < 0.05). CONCLUSIONS: The glycemic thresholds for activation of counterregulatory hormone and symptom responses appear normal after islet transplantation; however, the magnitudes of the glucagon and epinephrine responses remain impaired.

Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes.

Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypoglycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven control subjects underwent a paired hyperinsulinemic-euglycemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and control subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recipients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients compared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperinsulinemia during the euglycemic clamp and was significantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.

{beta}-Cell function following human islet transplantation for type 1 diabetes.

Islet transplantation can provide metabolic stability for patients with type 1 diabetes; however, more than one donor pancreas is usually required to achieve insulin independence. To evaluate possible mechanistic defects underlying impaired graft function, we studied five subjects at 3 months and four subjects at 12 months following intraportal islet transplantation who had received comparable islet equivalents per kilogram (12,601 +/- 1,732 vs. 14,384 +/- 2,379, respectively). C-peptide responses, as measures of beta-cell function, were significantly impaired in both transplant groups when compared with healthy control subjects (P < 0.05) after intravenous glucose (0.3 g/kg), an orally consumed meal (600 kcal), and intravenous arginine (5 g), with the greatest impairment to intravenous glucose and a greater impairment seen in the 12-month compared with the 3-month transplant group. A glucose-potentiated arginine test, performed only in insulin-independent transplant subjects (n = 5), demonstrated significant impairments in the glucose-potentiation slope (P < 0.05) and the maximal response to arginine (AR(max); P < 0.05), a measure of beta-cell secretory capacity. Because AR(max) provides an estimate of the functional beta-cell mass, these results suggest that a low engrafted beta-cell mass may account for the functional defects observed after islet transplantation.