Effects of Dietary Fat and Protein on Glucoregulatory Hormones in Adolescents and Young Adults With Type 1 Diabetes

Context Dietary fat and protein impact postprandial hyperglycemia in people with type 1 diabetes, but the underlying mechanisms are poorly understood. Glucoregulatory hormones are also known to modulate gastric emptying and may contribute to this effect. Objective Investigate the effects of fat and protein on glucagon-like peptide (GLP-1), glucagon-dependent insulinotropic polypeptide (GIP) and glucagon secretion. Methods 2 crossover euglycemic insulin clamp clinical trials at 2 Australian pediatric diabetes centers. Participants were 12-21 years (n = 21) with type 1 diabetes for ≥1 year. Participants consumed a low-protein (LP) or high-protein (HP) meal in Study 1, and low-protein/low-fat (LPLF) or high-protein/high-fat (HPHF) meal in Study 2, all containing 30 g of carbohydrate. An insulin clamp was used to maintain postprandial euglycemia and plasma glucoregulatory hormones were measured every 30 minutes for 5 hours. Data from both cohorts (n = 11, 10) were analyzed separately. The main outcome measure was area under the curve of GLP-1, GIP, and glucagon. Results Meals low in fat and protein had minimal effect on GLP-1, while there was sustained elevation after HP (80.3 ± 16.8 pmol/L) vs LP (56.9 ± 18.6), P = .016, and HPHF (103.0 ± 26.9) vs LPLF (69.5 ± 31.9) meals, P = .002. The prompt rise in GIP after all meals was greater after HP (190.2 ± 35.7 pmol/L) vs LP (152.3 ± 23.3), P = .003, and HPHF (258.6 ± 31.0) vs LPLF (151.7 ± 29.4), P < .001. A rise in glucagon was also seen in response to protein, and HP (292.5 ± 88.1 pg/mL) vs LP (182.8 ± 48.5), P = .010. Conclusion The impact of fat and protein on postprandial glucose excursions may be mediated by the differential secretion of glucoregulatory hormones. Further studies to better understand these mechanisms may lead to improved personalized postprandial glucose management.

The Obesity Risk SNP (rs17782313) near the MC4R Gene Is Not Associated with Brain Glucose Uptake during Insulin Clamp—A Study in Finns

The melanocortin system is involved in the control of adiposity through modulation of food intake and energy expenditure. The single nucleotide polymorphism (SNP) rs17782313 near the MC4R gene has been linked to obesity, and a previous study using magnetoencephalography has shown that carriers of the mutant allele have decreased cerebrocortical response to insulin. Thus, in this study, we addressed whether rs17782313 associates with brain glucose uptake (BGU). Here, [18F]-fluorodeoxyglucose positron emission tomography (PET) data from 113 Finnish subjects scanned under insulin clamp conditions who also had the rs17782313 determined were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. Statistical analysis was performed with statistical parametric mapping. There was no difference in age, BMI, and insulin sensitivity as indexed by the M value between the rs17782313-C allele carriers and non-carriers. Brain glucose uptake during insulin clamp was not different by gene allele, and it correlated with the M value, in both the rs17782313-C allele carriers and non-carriers. The obesity risk SNP rs17782313 near the MC4R gene is not associated with brain glucose uptake during insulin clamp in humans, and this frequent mutation cannot explain the enhanced brain glucose metabolic rates in insulin resistance.

Baseline Characteristics of Participants in a Randomized Controlled Trial of Metformin for Frailty Prevention

We are conducting a double-blind, randomized controlled trial of metformin for frailty prevention. Participants are adults aged 65+ years with pre-diabetes assessed by 2-hour oral glucose tolerance test (OGTT). Those who are frail (Fried criteria) are excluded. Participants are randomized to metformin (maximum dose of 2,000 mg/day) vs. placebo and followed for 2 years. The primary outcome is frailty (category and score); secondary outcomes are physical performance and function (short physical performance battery, 6-minute walk, lower extremity strength), systemic and skeletal muscle tissue inflammation, muscle insulin signaling, insulin sensitivity (insulin clamp), glucose tolerance (OGTT), and body composition (dual-energy x-ray absorptiometry). Safety assessments occur every 3 months; frailty, systemic inflammation, and OGTT are assessed at baseline and every 6 months, and insulin clamp with muscle biopsies are assessed at baseline and every 12 months. To date, 85 subjects have been randomized; 120 completers are planned. Mean age is 72.8 ± 5.7 years, 55.3% are male, and 43.5% were Hispanic. Mean BMI is 30.2±5.8 kg/m2, waist circumference is 104.4 ±15.5 cm, fasting glucose is 102.3 ± 10.0 mg/dL, Hemoglobin A1c is 5.8 ±0.3, and glucose at 2 hours during OGTT is 167.3 ± 17.8 mg/dL. Metformin is being examined in this study as a potential therapeutic agent to prevent frailty in older adults with pre-diabetes. Findings from this trial may have future implications for the screening and potential treatment of pre-diabetes in older patients with metformin for the prevention of frailty.

Adaptation of Insulin Clearance to Metabolic Demand is a Key Determinant of Glucose Tolerance

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action in order to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCR_I). <p>T2DM subjects (104 NGT, 57 IGT, and 207), divided in non-obese and obese groups, received a euglycemic insulin-clamp (40 mU/m².min) and OGTT (75-grams) on separate days. MCR_I was calculated during the insulin-clamp performed with 3-3H-glucose and the OGTT and related to IR: peripheral (glucose uptake during insulin clamp), hepatic (basal EGPxFPI), and adipocyte (fasting FFAxFPI).</p> <p>MCR_I during the insulin-clamp was reduced in obese versus non-obese NGT (0.60±0.03 vs 0.73±0.02 L/min.m², p<0.001), in non-obese IGT (0.62±0.02, p<0.004) and in non-obese T2DM (0.68±0.02, p<0.03). The MCR_I during the insulin-clamp was strongly and inversely correlated with IR (r=-0.52, p<0.0001). During OGTT the MCR_I suppressed within 15-30 minutes in NGT and IGT subjects and remained suppressed. In contrast, there was minimal suppression in T2DM. </p> <p>In conclusion, the development of IR in obese subjects is associated with decline in MCR_I that represents a compensatory response to maintain normal glucose tolerance but is impaired in T2DM individuals.</p>

Adaptation of Insulin Clearance to Metabolic Demand is a Key Determinant of Glucose Tolerance

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action in order to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCR_I). <p>T2DM subjects (104 NGT, 57 IGT, and 207), divided in non-obese and obese groups, received a euglycemic insulin-clamp (40 mU/m².min) and OGTT (75-grams) on separate days. MCR_I was calculated during the insulin-clamp performed with 3-3H-glucose and the OGTT and related to IR: peripheral (glucose uptake during insulin clamp), hepatic (basal EGPxFPI), and adipocyte (fasting FFAxFPI).</p> <p>MCR_I during the insulin-clamp was reduced in obese versus non-obese NGT (0.60±0.03 vs 0.73±0.02 L/min.m², p<0.001), in non-obese IGT (0.62±0.02, p<0.004) and in non-obese T2DM (0.68±0.02, p<0.03). The MCR_I during the insulin-clamp was strongly and inversely correlated with IR (r=-0.52, p<0.0001). During OGTT the MCR_I suppressed within 15-30 minutes in NGT and IGT subjects and remained suppressed. In contrast, there was minimal suppression in T2DM. </p> <p>In conclusion, the development of IR in obese subjects is associated with decline in MCR_I that represents a compensatory response to maintain normal glucose tolerance but is impaired in T2DM individuals.</p>

Regulation of ANGPTL8 in liver and adipose tissue by nutritional and hormonal signals and its effect on glucose homeostasis in mice

The angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal, and molecular regulation in key metabolic tissues. The regulation of Angptl8 gene expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in primary and cultured hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of Angptl8 was determined using bioinformatic and luciferase reporter approaches. The metabolism of Angptl8 knockout mice (ANGPTL8−/−) was examined following chow and high-fat diets (HFD). Insulin acutely increased Angptl8 expression in liver and adipose tissue, which involved the CCAAT/enhancer-binding protein (C/EBPβ) transcription factor. In insulin clamp experiments, glucose further enhanced Angptl8 expression in the presence of insulin in adipose tissue. The activation of AMPK signaling antagonized the effect of insulin on Angptl8 expression in hepatocytes and adipocytes. The ANGPTL8−/− mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no change in body weight or steatosis in ANGPTL8−/− mice after the HFD. These data show that ANGPTL8 plays important metabolic roles in mice that extend beyond triglyceride metabolism. The finding that insulin, glucose, and AMPK signaling regulate Angptl8 expression may provide important clues about the distinct function of ANGPTL8 in these tissues.

A RANDOMIZED CONTROLLED TRIAL OF METFORMIN FOR FRAILTY PREVENTION: STUDY DESIGN AND BASELINE CHARACTERISTICS

Inflammation and insulin resistance are major predictors of frailty. Here we describe the study design of an ongoing double-blind, randomized controlled trial of metformin for frailty prevention. Subjects are adults aged 65+ years with pre-diabetes assessed by 2-hour oral glucose tolerance test (OGTT). Those who are frail (Fried criteria) are excluded. Participants are randomized to metformin (maximum dose of 2,000 mg/day) vs. placebo and followed for 2 years. The primary outcome is frailty (category and score); secondary outcomes are physical performance and function (short physical performance battery, 6-minute walk, lower extremity strength), systemic and skeletal muscle tissue inflammation, muscle insulin signaling, insulin sensitivity (insulin clamp), glucose tolerance (OGTT), and body composition (dual-energy x-ray absorptiometry). Safety assessments occur every 3 months; frailty, systemic inflammation, and OGTT are assessed at baseline and every 6 months, and insulin clamp with muscle biopsies are assessed at baseline and every 12 months. To date, 51 subjects have been randomized; 120 completers are planned. Mean age is 73.4 ±5.7 years, 43% are female, and 39% Hispanic. Mean BMI is 30.5 ±5.5 kg/m2, waist circumference is 105 ±13.1 cm, fasting glucose is 102.3 ±8.8 mg/dL, Hemoglobin A1c is 5.8 ±0.3, and glucose at 2 hours during OGTT is 168.5 ±20.4 mg/dL. Metformin is being examined in this study as a potential therapeutic agent to prevent frailty in older adults with pre-diabetes. Findings from this trial may have future implications for the screening and potential treatment of pre-diabetes in older patients with metformin for the prevention of frailty.

The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling

ObjectiveThe angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal and molecular regulation in key metabolic tissues.MethodsThe metabolism of ANGPTL8 knockout mice (ANGPTL8−/−) was examined in mice following chow and high-fat diets (HFD). The regulation of ANGPTL8 expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of ANGPTL8 was determined using bioinformatic and luciferase reporter approaches.ResultsThe ANGPTL8−/−mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no reduction in steatosis in ANGPTL8−/−mice after the HFD. Insulin acutely activated ANGPTL8 expression in liver and adipose tissue, which was mediated by C/EBPβ. Using insulin clamp experiments we observed that glucose further enhanced ANGPTL8 expression in the presence of insulin in adipocytes only. The activation of AMPK signaling potently suppressed the effect of insulin on ANGPTL8 expression in hepatocytes.ConclusionThese data show that ANGPTL8 plays an important metabolic role in mice that may extend beyond triglyceride metabolism. The finding that insulin and glucose have distinct roles in regulating ANGPTL8 expression in liver and adipose tissue may provide important clues about the function of ANGPTL8 in these tissues.