Robert P. Hoffman

Young children ( 12 yr) with type 1 diabetes mellitus have low rate of partial remission: diabetic ketoacidosis is an important risk factor

Objective:  To determine whether there are different rates of partial remission in preschool, school‐age children, and adolescents with type 1 diabetes mellitus (T1DM) and to identify clinical characteristics that are associated with increased rate of partial remission.

Indices of insulin action calculated from fasting glucose and insulin reflect hepatic, not peripheral, insulin sensitivity in African-American and Caucasian adolescents

Abstract:  Insulin stimulates muscle glucose uptake and inhibits hepatic glucose production. Measures of insulin sensitivity or insulin resistance must take both of these actions into account. Homeostatic model assessment of insulin resistance (HOMAIR) and quantitative insulin sensitivity check index (QUICKI) are two simple measures of insulin resistance and insulin sensitivity that are derived from fasting glucose and insulin levels as such it is likely that they reflect primary hepatic insulin action and not muscular effects. To prove this hypothesis, the relationships of HOMAIR and QUICKI to peripheral insulin sensitivity (SI*) and hepatic insulin resistance (HIR) were assessed in 34 adolescents (age 13.5 ± 2.9 yr, body mass index 23.0 ± 5.7, mean ± SD; 16 Caucasian and 14 African‐American). SI* and HIR were determined using the stable‐labeled, frequently sampled intravenous glucose tolerance test (250 mg total glucose/kg, 13% [6,6]‐d2‐glucose). The former was calculated using the one‐compartment minimal model and stable glucose concentration (SI*), and the latter was determined over the last hour of the study by multiplying hepatic glucose production (Steele’s equation) by mean plasma insulin concentration. As expected, HOMAIR and QUICKI were significantly related to HIR (log HOMAIR and log HIR, r = 0.73, p < 0.001; QUICKI and log HIR, r = −0.69, p < 0.001) but not SI*. When both SI* and HIR were included in the equations, only the relationships to log HIR were significant (log HOMAIR, p < 0.001; QUICKI, p < 0.001). The relationships were similar in African‐American and Caucasian subjects. These results demonstrate that in adolescents, HOMAIR and QUICKI assess hepatic but not peripheral insulin action.

Hyperglycemia Increases Muscle Blood Flow and Alters Endothelial Function in Adolescents with Type 1 Diabetes

Alterations of blood flow and endothelial function precede development of complications in type 1 diabetes. The effects of hyperglycemia on vascular function in early type 1 diabetes are poorly understood. To investigate the effect of hyperglycemia on forearm vascular resistance (FVR) and endothelial function in adolescents with type 1 diabetes, FVR was measured before and after 5 minutes of upper arm arterial occlusion using venous occlusion plethysmography in (1) fasted state, (2) euglycemic state (~90 mg/dL; using 40 mU/m2/min insulin infusion), and (3) hyperglycemic state (~200 mg/dL) in 11 adolescents with type 1 diabetes. Endothelial function was assessed by the change in FVR following occlusion. Seven subjects returned for a repeat study with hyperglycemia replaced by euglycemia. Preocclusion FVR decreased from euglycemia to hyperglycemia (P = 0.003). Postocclusion fall in FVR during hyperglycemia was less than during euglycemia (P = 0.002). These findings were not reproduced when hyperglycemia was replaced with a second euglycemia. These results demonstrate that acute hyperglycemia causes vasodilation and alters endothelial function in adolescents with type 1 diabetes. In addition they have implications for future studies of endothelial function in type 1 diabetes and provide insight into the etiology of macrovascular and microvascular complications of type 1 diabetes.

Effect of Vitamins C and E on Endothelial Function in Type 1 Diabetes Mellitus

Background/Objectives. Endothelial dysfunction due to hyperglycemia-induced oxidative damage is an important predictor of future cardiovascular risk in patients with type 1 diabetes mellitus (T1DM) and is present in adolescent T1DM. We hypothesized that combined treatment with the antioxidant vitamins C and E might improve endothelial function (EF) and other biochemical risk factors in adolescents with T1DM. Subjects/Methods. Open-label antioxidant supplementation was given for six weeks with endpoint measurements collected at baseline and study completion. Endpoints measured included EF and plasma measurements of biochemical endothelial risk. Results. Two males and 7 females were studied. Mean age was 12.9 ± 0.9 yrs; mean T1DM duration was 5.5 ± 2.5 yrs; mean BMI was 22.1 ± 3.8 kg/m2; and mean hemoglobin A1c was 9.3 ± 1.1%. No differences were found for EF, high sensitivity CRP, total antioxidant capacity, adiponectin, or endothelial progenitor cells (EPCs) between before and after combined vitamin C and E therapy. Conclusions. Our negative study results do not support previous findings of decreased oxidative damage, improved endothelial function, and increased vascular repair capacity with antioxidant therapy. Longer term studies may be needed to determine the effects, if any, of combined antioxidant therapy on EPCs, EF, and markers of micro- and macrovascular complications in T1DM.

Pubertal changes in HOMA and QUICKI: relationship to hepatic and peripheral insulin sensitivity

Abstract:  Background:  Homeostasis model assessment (HOMA) and quantitative insulin‐sensitivity check index (QUICKI) are measures of insulin resistance and insulin sensitivity derived from fasting glucose (FG) and insulin levels. They thus should reflect, in principle, insulin action on both the liver and the periphery.

Triple diabetes: coexistence of type 1 diabetes mellitus and a novel mutation in the gene responsible for MODY3 in an overweight adolescent

Abstract:  We report an interesting and unique case of an overweight adolescent with a novel mutation of the maturity‐onset diabetes of the young (MODY)3 gene [hepatocyte nuclear factor‐1 alpha (HNF‐1α)] and positive islet cell autoantibodies. The patient is a 17‐yr‐old Caucasian female, who was diagnosed with type 2 diabetes mellitus, treated with metformin and glipizide, with poor control for 18 months prior to being referred to the Endocrinology clinic. Family history was strongly positive for type 2 diabetes (father, paternal aunts, uncles, and grandmother). All were diagnosed at age 40–50 and treated with oral hypoglycemic agents. The patient’s body mass index was 36.4 kg/m2. She had no acanthosis nigricans. Initial hemoglobin A1c was 11.9%, with fasting glucose of 234 mg/dL and fasting insulin 10.7 μU/mL. She was started on insulin therapy (0.6 units/kg/d), resulting in good glycemic control. Oral hypoglycemic agents were discontinued. Immunologic studies showed positive islet cell (29 U/mL, normal <1.0) and glutamic acid decarboxylase‐65 (0.9 U/mL, normal <0.5) antibodies. Sequencing for HNF‐1α gene revealed a nucleotide A to G substitution (ACC to GCC), resulting in a missense mutation, T196A. To our knowledge, T196A has not been previously reported. The coexistence of type 1 diabetes autoimmunity and a mutation in the gene responsible for MODY3 in this overweight patient is intriguing and might explain the early onset of progressive insulinopenia compared with the later age of diabetes onset of the earlier generation in the family.

Practical Management of Type 1 Diabetes Mellitus in Adolescent Patients

Type 1 diabetes mellitus in adolescents presents diagnostic and management challenges. Diagnostically, the challenge is to distinguish type 1 from type 2 diabetes. A thin adolescent in diabetic ketoacidosis is easily recognized as having type 1 diabetes. However, since obesity does not negate the presence of type 1 diabetes, it is appropriate to measure diabetes-related antibody, C-peptide, and insulin levels in individuals who are thought to have type 2 diabetes to ensure that they do not have type 1 or a mixed type of diabetes.The goals for the management of type 1 diabetes in adolescents are to (i) prevent diabetic ketoacidosis; (ii) prevent severe hypoglycemia; (iii) maintain normal growth and development; and (iv) prevent long-term diabetic complications. To prevent diabetic ketoacidosis, patients must take their insulin appropriately. To ensure that this happens, increased parental supervision, psychological counseling, or placement in a different home environment may be necessary. All patients must be taught to appropriately manage sick days and test their urine for ketones when hyperglycemia is present.Prevention of severe hypoglycemia involves ensuring that the patient understands the symptoms of hypoglycemia and knows to test and treat it when the signs are present. Patients and families also need to know how to adjust insulin doses to prevent hypoglycemia and how to manage exercise appropriately. Patients with hypoglycemic unawareness need to meticulously avoid hypoglycemia.To maintain normal growth and development, adolescents with type 1 diabetes must have the appropriate tools to effectively match their meals to their lifestyle and to avoid the increased weight gain associated with improved glycemic control without intentionally manipulating their insulin dose to lose weight.The Diabetes Control and Complications Trial demonstrated that improved glycemic control decreased the risk of long-term diabetic complications. The goals of treatment in this study should be the goals for all adolescents with type 1 diabetes. To reach these goals, home glucose monitoring is critical. Patients need to know how to adjust insulin to maintain glucose levels in the range of 70–120 mg/dL (3.9–6.7 mmol/L) before meals. Insulin regimens need to be individually tailored to meet each patient’s needs.Patients should be followed in a clinic using a multidisciplinary team approach at least every 3 months. Glycosylated hemoglobin should be measured at each visit. Regular eye exams, blood pressure monitoring, and urinary microalbumin measurements are critical. In this manner, the goals of management of type 1 diabetes in adolescents can be met.

Ascorbic acid blocks hyperglycemic impairment of endothelial function in adolescents with type 1 diabetes.

To determine whether acute ascorbic acid infusions alter the effect of hyperglycemia on endothelial function in adolescents with type 1 diabetes.

Glycemic variability predicts inflammation in adolescents with type 1 diabetes.

Abstract Background: Adolescents with type 1 diabetes (T1D) have increased risk of cardiovascular disease as well as elevations in biomarkers of systemic inflammation, plasma protein oxidation and vascular endothelial injury. It is unclear whether hyperglycemia itself, or variations in blood glucose are predictors of these abnormalities. Methods: This study was designed to determine the relationship of inflammatory (C-reactive protein, CRP), oxidative (total anti-oxidative capacity, TAOC) and endothelial injury (soluble intracellular adhesion molecule 1, sICAM1) markers to glycemic control measures from 3 days of continuous glucose monitoring (CGM) and to hemoglobin A1c (HbA1c), and HbA1c×duration area under the curve (A1cDur). Results: Seventeen adolescents (8 F/9M; age, 13.1±1.6 years (mean±SD); duration, 4.8±3.8 years, BMI, 20.3±3.1 kg/m2; A1c, 8.3±1.2%) were studied. Log CRP but was not related to age, duration, body mass index (BMI), HbA1c, or A1cDUR. TAOC increased as logA1cDUR increased (n=13, r=0.61, p=0.028). CRP and sICAM were not related to CGM average glucose but log CRP increased as 3 day glucose standard deviation increased (r=0.66, p=0.006). TAOC increased as glucose standard deviation increased (r=0.63, p=0.028). Conclusions: Increased glucose variability is associated with increased inflammation in adolescents withT1D. Increased TAOC with increasing variability may be an effort to compensate for the ongoing oxidative stress.

Gene CNVs and protein levels of complement C4A and C4B as novel biomarkers for partial disease remissions in new‐onset type 1 diabetes patients

To determine the roles of complement C4A and C4B gene copy‐number variations and their plasma protein concentrations in residual insulin secretion and loss of pancreatic β‐cell function in new‐onset type 1 diabetes (T1D) patients.