William V. Tamborlane

Continuous glucose monitoring and intensive treatment of type 1 diabetes

BACKGROUND The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

Impaired insulin action in puberty: a contributing factor to poor glycemic control in adolescents with diabetes

Patients with insulin-dependent diabetes mellitus often have poor metabolic control during puberty. To determine whether puberty is associated with decreased insulin-stimulated glucose metabolism, we compared the results of euglycemic insulin-clamp studies in adults and prepubertal and pubertal children with and without insulin-dependent diabetes. In nondiabetic pubertal children, insulin-stimulated glucose metabolism (201 +/- 12 mg per square meter of body surface area per minute) was sharply reduced, as compared with that of prepubertal children and adults (316 +/- 34 and 290 +/- 21 mg per square meter, respectively; P less than 0.01), despite comparable hyperinsulinemia (insulin levels of 80 to 90 microU per milliliter). Similarly, the response to insulin was 25 to 30 percent lower in the diabetic pubertal children than in the diabetic prepubertal children (P less than 0.05) and adults (P = 0.07). At each stage of development, the stimulating effect of insulin on glucose metabolism was decreased by 33 to 42 percent in the children with diabetes (P less than 0.01). In all the groups of children studied, the response to insulin was inversely correlated with mean 24-hour levels of growth hormone (r = -0.52, P = 0.01). Among the diabetic children, the glycosylated hemoglobin levels were substantially higher in the pubertal children than in the prepubertal children (P less than 0.02), although the daily insulin doses tended to be higher. These data suggest that insulin resistance occurs during puberty in both normal children and children with diabetes. The combined adverse effects of puberty and diabetes on insulin action may help explain why control of glycemia is so difficult to achieve in adolescent patients.

Effectiveness of Sensor-Augmented Insulin-Pump Therapy in Type 1 Diabetes

BACKGROUND Recently developed technologies for the treatment of type 1 diabetes mellitus include a variety of pumps and pumps with glucose sensors. METHODS In this 1-year, multicenter, randomized, controlled trial, we compared the efficacy of sensor-augmented pump therapy (pump therapy) with that of a regimen of multiple daily insulin injections (injection therapy) in 485 patients (329 adults and 156 children) with inadequately controlled type 1 diabetes. Patients received recombinant insulin analogues and were supervised by expert clinical teams. The primary end point was the change from the baseline glycated hemoglobin level. RESULTS At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the pump-therapy group, as compared with 8.1% in the injection-therapy group (P<0.001). The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the pump-therapy group than in the injection-therapy group. The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person-years) did not differ significantly from that in the injection-therapy group (13.48 per 100 person-years, P=0.58). There was no significant weight gain in either group. CONCLUSIONS In both adults and children with inadequately controlled type 1 diabetes, sensor-augmented pump therapy resulted in significant improvement in glycated hemoglobin levels, as compared with injection therapy. A significantly greater proportion of both adults and children in the pump-therapy group than in the injection-therapy group reached the target glycated hemoglobin level. (Funded by Medtronic and others; ClinicalTrials.gov number, NCT00417989.)

Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning

BACKGROUND Impaired glucose tolerance is common among obese adolescents, but the changes in insulin sensitivity and secretion that lead to this prediabetic state are unknown. We investigated whether altered partitioning of myocellular and abdominal fat relates to abnormalities in glucose homoeostasis in obese adolescents with prediabetes. METHODS We studied 14 obese children with impaired glucose tolerance and 14 with normal glucose tolerance, of similar ages, sex distribution, and degree of obesity. Insulin sensitivity and secretion were assessed by the euglycaemic-hyperinsulinaemic clamp and the hyperglycaemic clamp. Intramyocellular lipid was assessed by proton nuclear magnetic resonance spectroscopy and abdominal fat distribution by magnetic resonance imaging. FINDINGS Peripheral glucose disposal was significantly lower in individuals with impaired than in those with normal glucose tolerance (mean 35.4 [SE 4.0] vs 60.6 [7.2] micromoles per kg lean body mass per min; p=0.023) owing to a reduction in non-oxidative glucose disposal metabolism (storage). Individuals with impaired glucose tolerance had higher intramyocellular lipid content (3.04 [0.43] vs 1.99 [0.19]%, p=0.03), lower abdominal subcutaneous fat (460 [47] vs 626 [39] cm2, p=0.04), and slightly higher visceral fat than the controls (70 [11] vs 47 [6] cm2, p=0.065), resulting in a higher ratio of visceral to subcutaneous fat (0.15 [0.02] vs 0.07 [0.01], p=0.002). Intramyocellular and visceral lipid contents were inversely related to the glucose disposal and non-oxidative glucose metabolism and positively related to the 2 h plasma glucose concentration. INTERPRETATION In obese children and adolescents with prediabetes, intramyocellular and intra-abdominal lipid accumulation is closely linked to the development of severe peripheral insulin resistance.

Current State of Type 1 Diabetes Treatment in the U.S.: Updated Data From the T1D Exchange Clinic Registry

To examine the overall state of metabolic control and current use of advanced diabetes technologies in the U.S., we report recent data collected on individuals with type 1 diabetes participating in the T1D Exchange clinic registry. Data from 16,061 participants updated between 1 September 2013 and 1 December 2014 were compared with registry enrollment data collected from 1 September 2010 to 1 August 2012. Mean hemoglobin A1c (HbA1c) was assessed by year of age from <4 to >75 years. The overall average HbA1c was 8.2% (66 mmol/mol) at enrollment and 8.4% (68 mmol/mol) at the most recent update. During childhood, mean HbA1c decreased from 8.3% (67 mmol/mol) in 2–4-year-olds to 8.1% (65 mmol/mol) at 7 years of age, followed by an increase to 9.2% (77 mmol/mol) in 19-year-olds. Subsequently, mean HbA1c values decline gradually until ∼30 years of age, plateauing at 7.5–7.8% (58–62 mmol/mol) beyond age 30 until a modest drop in HbA1c below 7.5% (58 mmol/mol) in those 65 years of age. Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) remain all too common complications of treatment, especially in older (SH) and younger patients (DKA). Insulin pump use increased slightly from enrollment (58–62%), and use of continuous glucose monitoring (CGM) did not change (7%). Although the T1D Exchange registry findings are not population based and could be biased, it is clear that there remains considerable room for improving outcomes of treatment of type 1 diabetes across all age-groups. Barriers to more effective use of current treatments need to be addressed and new therapies are needed to achieve optimal metabolic control in people with type 1 diabetes.

Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats.

The ventromedial hypothalamic nucleus (VMH) is necessary for the integrated hormonal response to hypoglycemia. To determine the role of the VMH as a glucose sensor, we performed experiments designed to specifically prevent glucopenia in the VMH, while producing hypoglycemia elsewhere. We used awake chronically catheterized rats, in which local VMH glucose perfusion (100 mM or 15 mM of D-glucose) was combined with a sequential euglycemic-hypoglycemic clamp. In two control groups the VMH was perfused either with (a) an iso-osmotic solution lacking glucose, or with (b) nonmetabolizable L-glucose (100 mM). During systemic hypoglycemia glucagon and catecholamine concentrations promptly increased in the control animals perfused with either 100 mM L-glucose or the iso-osmotic solution lacking glucose. In contrast, glucagon, epinephrine and norepinephrine release was inhibited in the animals in which the VMH was perfused with D-glucose; hormonal secretion was partially suppressed by the VMH perfusion with 15 mM D-glucose and suppressed by approximately 85% when the VMH was perfused with 100 mM D-glucose, as compared with the control groups. We conclude that the VMH must sense hypoglycemia for full activation of catecholamine and glucagon secretion and that it is a key glucose sensor for hypoglycemic counterregulation.

Effect of Intensive Insulin Therapy on Glycemic Thresholds for Counterregulatory Hormone Release

To evaluate the effect of strict glycemie control of insulin-dependent diabetes mellitus (IDDM) on the plasma glucose threshold initiating counterregulatory hormone responses to hypoglycemia, we used the glucose clamp technique to produce a standardized gradual glucose decline from 90 to 40 mg/dl in seven young IDDM patients before and after 2–6 mo of intensified insulin therapy. Before intensive therapy [hemoglobin A1 (HbA1) 9.6 ± 1.1%], epinephrine responses were triggered at a higher plasma glucose level (67 ± 4 mg/dl) than in normal control subjects (56 ± 1 mg/dl, P < .05), and clinical symptoms of hypoglycemia appeared at glucose levels of 50–60 mg/dl. After intensive therapy (HbA, 7.1 ± 0.7%), the glucose threshold for epinephrine release consistently declined to values (46 ± 2 mg/dl) below normal (P < .01). Furthermore, epinephrine concentrations were markedly reduced at each hypoglycemie level, and a greater hypoglycemie stimulus was required to elicit symptoms. The glucose threshold stimulating release of growth hormone also significantly declined after intensive therapy. We conclude that strict glycemie control of IDDM lowers the plasma glucose level required to generate epinephrine release during hypoglycemia. This may diminish patient recognition of moderate hypoglycemia and increase the risk of severe hypoglycemia in intensively treated IDDM.

The effect of continuous glucose monitoring in well-controlled type 1 diabetes.

OBJECTIVE The potential benefits of continuous glucose monitoring (CGM) in the management of adults and children with well-controlled type 1 diabetes have not been examined. RESEARCH DESIGN AND METHODS A total of 129 adults and children with intensively treated type 1 diabetes (age range 8–69 years) and A1C <7.0% were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level ≤70 mg/dl, A1C level, and severe hypoglycemic events. RESULTS At 26 weeks, biochemical hypoglycemia (≤70 mg/dl) was less frequent in the CGM group than in the control group (median 54 vs. 91 min/day), but the difference was not statistically significant (P = 0.16). Median time with a glucose level ≤60 mg/dl was 18 versus 35 min/day, respectively (P = 0.05). Time out of range (≤70 or >180 mg/dl) was significantly lower in the CGM group than in the control group (377 vs. 491 min/day, P = 0.003). There was a significant treatment group difference favoring the CGM group in mean A1C at 26 weeks adjusted for baseline (P < 0.001). One or more severe hypoglycemic events occurred in 10 and 11% of the two groups, respectively (P = 1.0). Four outcome measures combining A1C and hypoglycemia data favored the CGM group in comparison with the control group (P < 0.001, 0.007, 0.005, and 0.003). CONCLUSIONS Most outcomes, including those combining A1C and hypoglycemia, favored the CGM group. The weight of evidence suggests that CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%.

Increased insulin secretion in puberty: A compensatory response to reductions in insulin sensitivity

Recent studies have suggested that insulin action is reduced during puberty in normal children. To determine whether such resistance leads to excessive insulin secretion, we used the hyperglycemic clamp technique to produce a standard hyperglycemic stimulus (125 mg/dl above fasting levels for 120 minutes) in 9 preadolescent and 14 adolescent healthy children and in 14 normal adults. Fasting plasma insulin and C-peptide concentrations were higher in adolescents than in preadolescents and adults (p less than or equal to 0.02). Despite identical glucose increments during the glucose clamp procedure, both first- and second-phase plasma insulin and C-peptide responses were also markedly greater in adolescents than in preadolescents or adults (p less than 0.01 vs. other groups). Despite sharply increased insulin responses in adolescents, the amount of exogenous glucose required to maintain hyperglycemia was similar in all three groups. Insulin responses in the children were directly correlated with fasting plasma levels of insulin-like growth factor I (r = 0.60 to 0.70, p less than 0.01). We conclude that glucose-stimulated insulin secretion is normally increased during puberty, a response that may compensate for puberty-induced defects in insulin sensitivity.

Defective Glucose Counterregulation after Strict Glycemic Control of Insulin-Dependent Diabetes Mellitus

We infused small doses of insulin (0.3 mU per kilogram of body weight per minute; range, 0.9 to 1.7 U per hour) for three hours into 8 subjects who did not have diabetes, 11 patients with well-controlled diabetes (hemoglobin A1, 7.6 +/- 0.7 percent), and 10 patients with poorly controlled diabetes (hemoglobin A1, 11.5 +/- 1.7 percent) to simulate the mild peripheral hyperinsulinemia observed during insulin treatment. Normoglycemia was established in the patients during the night before study. During the insulin infusion, the plasma glucose level stabilized at 60 to 70 mg per deciliter (3.3 to 3.9 mmol per liter) in the subjects without diabetes and the patients with poorly controlled diabetes, because of a rebound increase in hepatic glucose production. In contrast, hypoglycemia developed in the patients with well-controlled diabetes (42 +/- 2 mg of glucose per deciliter, or 2.3 +/- 0.1 mmol per liter, P less than 0.01) as glucose production remained suppressed. The hypoglycemia in the patients with well-controlled diabetes was associated with a lowering of the plasma threshold of glucose that triggered a release of epinephrine (less than 45 mg of glucose per deciliter, or 2.5 mmol per liter, vs. greater than 55 mg per deciliter, or 3.1 mmol per liter, in the other groups, P less than 0.01) as well as an enhanced sensitivity to the suppressive effects of insulin on hepatic glucose production. Nearly identical disturbances in glucose counterregulation and decreased perception of hypoglycemia developed when four of the subjects with poorly controlled diabetes were restudied after intensive treatment. We conclude that strict control of diabetes induces physiologic alterations (delayed release of epinephrine and persistent suppression of glucose production) that impair glucose counterregulation to doses of insulin in the therapeutic range. These defects may contribute to the increased incidence of severe hypoglycemia reported during intensive insulin therapy.