Clearance Rate Of Insulin Research Articles

Moderate Weight Loss Improves Body Composition and Metabolic Function in Metabolically Unhealthy Lean Subjects.

Individuals who have "metabolically obese normal weight" (MONW) have an increased risk for cardiometabolic disease. Moderate weight loss has multiple benefits in people with obesity, but its effects in lean people are unknown. Thus, the effects of diet-induced 5% weight loss on body composition and metabolic function in MONW subjects were evaluated. Total body fat, visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) volumes, intrahepatic and intramyocellular lipid contents, insulin sensitivity (hyperinsulinemic-euglycemic clamp), glucose tolerance, and postprandial insulin secretion and clearance rates (mixed meal with minimal modeling) were measured before and after 4.8% ± 0.5% weight loss in 11 MONW Asians (48 ± 3 years old, six men and five women, BMI 22.7 ± 0.4 kg/m2 ). Weight loss decreased total fat mass by ∼9%, VAT and SAT volumes by ∼11% and ∼17%, respectively, and intrahepatic fat by ∼50% (all P < 0.05). Fasting plasma insulin, triglyceride, and total low- and high-density lipoprotein cholesterol concentrations were also reduced (P < 0.05). Insulin sensitivity indexes (M-value and M/I ratio) increased by 21% to 26% (both P < 0.05); β-cell responsivity and postprandial insulin secretion rate did not change, but insulin clearance rate increased by 16% (P < 0.05). Diet-induced moderate weight loss improves body composition, lipid profile, and insulin sensitivity and thereby reduces cardiometabolic risk in MONW Asians.

Assessment of hepatic insulin extraction from in vivo surrogate methods of insulin clearance measurement.

Hyperinsulinemia, accompanied by reduced first-pass hepatic insulin extraction (FPE) and increased secretion, is a primary response to insulin resistance. Different in vivo methods are used to estimate the clearance of insulin, which is assumed to reflect FPE. We compared two methodologically different but commonly used indirect estimates with directly measured FPE in healthy dogs ( n = 9). The indirect methods were 1) metabolic clearance rate of insulin (MCR) during the hyperinsulinemic-euglycemic clamp (EGC), a steady-state method, and 2) fractional clearance rate of insulin (FCR) during the frequently sampled intravenous glucose tolerance test (FSIGT), a dynamic method. MCR was calculated as the ratio of insulin infusion rate to steady-state plasma insulin. FCR was calculated as the exponential decay rate constant of the injected insulin. Directly measured FPE is based on the difference in insulin measurements during intraportal vs. peripheral vein insulin infusions. We found a strong correlation between indirect FCR (min-1) and FPE (%). In contrast, we observed a poor association between MCR (ml·min-1·kg-1) and FPE (%). Our findings in canines suggest that FCR measured during FSIGT can be used to estimate FPE. However, MCR calculated during EGC appears to be a poor surrogate for FPE.

Adapting to insulin resistance in obesity: role of insulin secretion and clearance.

The aim of this study was to quantify the relative contributions of increased insulin secretion rate (ISR) and decreased insulin clearance rate (ICR) in the compensatory hyperinsulinaemia characteristic of insulin-resistant individuals without diabetes. Obese (BMI ≥30kg/m2) individuals without diabetes (n = 91) were identified from a registry of volunteers. Volunteers underwent the following measurements: oral glucose tolerance; insulin resistance (steady-state plasma glucose [SSPG] concentration during the insulin suppression test [IST]); ISR (using the graded glucose infusion test [GGIT]); and ICR (using the IST and GGIT). Participants were stratified into tertiles based on SSPG concentration: SSPG-1(insulin-sensitive); SSPG-2 (intermediate); and SSPG-3 (insulin-resistant). There were no differences in BMI and waist circumference among the SSPG tertiles. Serum alanine aminotransferase concentrations were higher in the SSPG-2 and SSPG-3 groups compared with the SSPG-1 group (p = 0.02). Following an oral glucose challenge, there was a progressive increase in the total integrated insulin response from the most insulin-sensitive to the most insulin-resistant tertiles (p < 0.001). Following intravenous glucose, the SSPG-3 group had significantly greater integrated glucose (median [interquartile range], 32.9 [30.8-36.3] mmol/l × h) and insulin responses (1711 [1476-2223] mmol/l × h) compared with the SSPG-1 group (30.3 [28.8-32.9] mmol/l × h, p = 0.04, and 851 [600-1057] pmol/l × h, p < 0.001, respectively). Furthermore, only the SSPG-3 group had significant changes in both ISR and ICR (p < 0.001). In the SSPG-2 group, only the ICR was significantly decreased compared with the SSPG-1 group. Therefore, ICR progressively declined during the IST with increasing insulin resistance (SSPG-1, 0.48 [0.41-0.59]; SSPG-2, 0.43 [0.39-0.50]; SSPG-3, 0.34 [0.31-0.40]). While both increases in ISR and decreases in ICR compensate for insulin resistance, decreases in ICR may provide the first adaptation to decreased insulin sensitivity.

Maternal methyl donor and cofactor supplementation in late pregnancy increases β-cell numbers at 16 days of life in growth-restricted twin lambs.

Restricted growth before birth (IUGR) increases adult risk of Type 2 diabetes by impairing insulin sensitivity and secretion. Altered fetal one-carbon metabolism is implicated in developmental programming of adult health and disease by IUGR. Therefore, we evaluated effects of maternal dietary supplementation with methyl donors and cofactors (MMDS), designed to increase fetal supply, on insulin action in the spontaneously IUGR twin lamb. In vivo glucose-stimulated insulin secretion and insulin sensitivity were measured at days 12-14 in singleton controls (CON, n = 7 lambs from 7 ewes), twins (IUGR, n = 8 lambs from 8 ewes), and twins from ewes that received MMDS (2 g rumen-protected methionine, 300 mg folic acid, 1.2 g sulfur, 0.7 mg cobalt) daily from 120 days after mating (~0.8 of term) until delivery (IUGR+MMDS, n = 8 lambs from 4 ewes). Body composition and pancreas morphometry were assessed in lambs at day 16 IUGR reduced size at birth and increased neonatal fractional growth rate. MMDS normalized long bone lengths but not other body dimensions of IUGR lambs at birth. IUGR did not impair glucose control or insulin action at days 12-14, compared with controls. MMDS increased metabolic clearance rate of insulin and increased β-cell numerical density and tended to improve insulin sensitivity, compared with untreated IUGR lambs. This demonstrates that effects of late-pregnancy methyl donor supplementation persist until at least the third week of life. Whether these effects of MMDS persist beyond early postnatal life and improve metabolic outcomes after IUGR in adults and the underlying mechanisms remain to be determined.

Correlates of insulin clearance in apparently healthy non-obese Japanese men

Hyperinsulinemia observed in obese subject is caused at least in part by low metabolic clearance rate of insulin (MCRI). However, the determinants of MCRI in non-obese subjects are not fully understood. To investigate the correlates of MCRI in healthy non-obese men (BMI <25 kg/m2), we studied 49 non-obese Japanese men free of cardiometabolic risk factors. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and insulin sensitivity. We also calculated the rate of glucose disappearance (Rd) during the clamp and muscle insulin sensitivity was defined as Rd/steady state serum insulin (SSSI) at the second step. Based on the median value of MCRI, the subjects were divided into the low- and high-MCRI groups. Subjects of the low-MCRI group had significant impairment of muscle insulin sensitivity, although Rd levels were comparable between the two groups, probably due to elevated SSSI in the low-MCRI group. Subjects of the low-MCRI group had higher total body fat content and lower VO2peak and showed no deterioration of cardiometabolic risk factors. Our results suggest that low MCRI may be early change to maintain glucose uptake and metabolic status in the face of slight impairment of muscle insulin sensitivity caused by increased adiposity and lower fitness level.

Short communication: Limitations of glucose tolerance tests in the assessment of peripheral tissue insulin sensitivity during pregnancy and lactation in dairy heifers

The aim of the present study was to point at the limitations of glucose tolerance tests (GTT) to assess peripheral tissue insulin sensitivity in dairy heifers in different physiological states (pregnancy and lactation). Intravenous GTT were performed in 5 nonpregnant, nonlactating heifers, 5 heifers at the end of pregnancy (12-7 d before calving), and 5 lactating primiparous cows (11-14 d after calving). Glucose and insulin concentrations were determined and area under the curve (AUC) and clearance rate of glucose and insulin were calculated. Additionally, data were analyzed using the minimal model to derive the insulin sensitivity parameter (Si). Basal glucose and insulin concentrations were greater in the nonpregnant, nonlactating heifers. Clearance rate of glucose and Si were lowest, whereas the AUC for glucose was greatest in the nonpregnant, nonlactating heifers. Insulin concentrations during the GTT were greater for the nonpregnant, nonlactating heifers. Results from the GTT in pregnant heifers and lactating primiparous cows are biased by the fact that a large part of the glucose disappearance during an intravenous GTT occurs independently of insulin by the pregnant uterus or the lactating mammary gland. As such, greater AUC of glucose, lower clearance rate of glucose, or lower Si derived from GTT performed in nonpregnant, nonlactating dairy heifers in the present study might indicate decreased peripheral tissue insulin sensitivity of the glucose metabolism or decreased insulin-independent glucose disappearance. Based on the results from a GTT, it is impossible to discriminate between both metabolic pathways. It can be concluded that parameters derived from GTT are not suited to compare peripheral tissue insulin sensitivity of the glucose metabolism between dairy heifers in different physiological states due to the large variation in insulin secretion and the substantial difference in insulin-independent glucose disposal associated with these physiological states.

Dissecting the relationship between obesity and hyperinsulinemia: Role of insulin secretion and insulin clearance.

OBJECTIVEThe aim of this study was to better delineate the complex interrelationship among insulin resistance (IR), secretion rate (ISR) and clearance rate (ICR) to increase plasma insulin concentrations in obesity.METHODSHealthy volunteers (92 non-diabetic individuals) had an insulin suppression test (IST) to measure IR, and graded-glucose infusion test (GGIT) to measure ISR and ICR. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2, and IR was defined as steady-state plasma glucose (SSPG) ≥ 10 mmol/L during the IST. We compared plasma glucose and insulin concentrations, ISR, and ICR in 3 groups: insulin sensitive/overweight (IS-OW); insulin sensitive/obese (IS-OB); and insulin resistant/obese (IR-OB).RESULTSCompared with IS-OW, IS-OB had significantly higher insulin area under the curve (AUC) and ISR AUC during the GGIT (P<0.001). Glucose AUC and ICR were similar. IR-OB had higher insulin AUC and ISR AUC compared with IS-OB but also had higher glucose AUC and decreased ICR (P<0.01). In multivariate analysis, both BMI and SSPG were significantly associated with ISR.CONCLUSIONSPlasma insulin concentration and ISR are increased in individuals with obesity, irrespective of degree of IR, but a decrease in ICR is confined to the subset of individuals who are IR.

Insulin Clearance Is Associated with Hepatic Lipase Activity and Lipid and Adiposity Traits in Mexican Americans.

Reduction in insulin clearance plays an important role in the compensatory response to insulin resistance. Given the importance of this trait to the pathogenesis of diabetes, a deeper understanding of its regulation is warranted. Our goal was to identify metabolic and cardiovascular traits that are independently associated with metabolic clearance rate of insulin (MCRI). We conducted a cross-sectional analysis of metabolic and cardiovascular traits in 765 participants from the Mexican-American Coronary Artery Disease (MACAD) project who had undergone blood sampling, oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, dual-energy X-ray absorptiometry, and carotid ultrasound. We assessed correlations of MCRI with traits from seven domains, including anthropometry, biomarkers, cardiovascular, glucose homeostasis, lipase activity, lipid profile, and liver function tests. We found inverse independent correlations between MCRI and hepatic lipase (P = 0.0004), insulin secretion (P = 0.0002), alanine aminotransferase (P = 0.0045), total fat mass (P = 0.014), and diabetes (P = 0.03). MCRI and apolipoprotein A-I exhibited a positive independent correlation (P = 0.035). These results generate a hypothesis that lipid and adiposity associated traits related to liver function may play a role in insulin clearance.

Determining insulin sensitivity from glucose tolerance tests in sheep.

A mathematical model of the dynamics of insulin and glucose during a frequently sampled intravenous glucose tolerance test (IVGTT) in sheep was developed that characterizes the large second-phase insulin secretion response in sheep during IVGTT. The model was fit to measurements of the glucose and insulin dynamics during standard IVGTT ( = 42) and modified IVGTT ( = 40), where insulin was injected 60 min after the initiation of the IVGTT. The correlation between log insulin sensitivity determined by hyperglycemic clamps (HGC) and standard IVGTT was = 0.43 ( = 0.005). The correlation between log insulin sensitivity determined by HGC and modified IVGTT was = 0.51 ( = 0.002). The model, therefore, provides a method to determine insulin sensitivity through a cheaper and more easily performed IVGTT. We validated our estimation procedure using 2 independent experiments on the effect of 1) pregnancy and 2) being born preterm and exposed to dextrose or dextrose with insulin on HGC-derived insulin sensitivity. The IVGTT-derived insulin sensitivity was significantly greater in pregnant ewes than in prepregnant ewes (difference of 0.39 ± 0.12 log n ng mL; < 0.05), and this was consistent with the significantly greater hyperinsulinemic euglycemic clamp-derived insulin sensitivity in pregnant ewes than in prepregnant ewes (difference of 4.03 ± 0.66 µmol mL kg min ng; < 0.001). There was no significant effect of being born preterm on IVGTT/HGC-derived insulin sensitivity. Basal insulin, insulin sensitivity, insulin production, and insulin clearance were lower in prepregnant ewes ( < 0.05). That is, prepregnant ewes have a lower insulin equilibrium status and less responsive insulin turnover. There was also a significant effect of insulin therapy on the rate of insulin clearance in preterm lambs ( < 0.05). This effect was independently significant of its covariance with all other model parameters. Therefore, it can be interpreted as a direct effect on the rate of insulin clearance by the insulin treatment. All other parameter responses to the insulin treatment effect can be regarded as being due to the covariance between these parameters. These analyses demonstrate that treatment effects on insulin sensitivity can be detected using IVGTT experiments.

Incorporating bolus and infusion pharmacokinetics into the ICING insulin model

The ICING model has been successfully used to guide clinical decisions on insulin administration in critical illness. However, insulin pharmacokinetics in the ICING model can be improved to better describe both intravenous (IV) bolus and infusion insulin administration. Patient data from 217 Dynamic Insulin Sensitivity and Secretion Tests (DISST) and 36 Intravenous Glucose Tolerance Tests (IVGTT) from independent dietary intervention studies was used to fit model parameters to a model structure that conforms to known behaviour. The DISST tests measured both endogenous and exogenous IV insulin bolus responses, while the IVGTT measured exogenous IV insulin infusion dynamics. Unidentifiable parameters were given physiologically justified values, with knowledge on relative insulin clearance rates used to constrain parameter values. The resulting whole-cohort description was able to simultaneously describe both IV bolus and infusion dynamics, and improves ICING model descriptive capability. Improved infusion dynamics will allow better description of subcutaneous insulin, the insulin administration route favoured in outpatient care of diabetes.

Insulin clearance: an underappreciated modulator of plasma insulin concentration

Plasma glucose concentrations are tightly regulated and maintained within a narrow range in non-diabetic individuals. Maintenance of this physiological state is primarily a function of the ability of the pancreatic...

Effects of diet-induced weight gain and turnout to pasture on insulin sensitivity in moderately insulin resistant horses.

To quantify insulin sensitivity and monitor glucose, insulin, and lipid concentrations in a group of moderately insulin-resistant horses during induction of obesity by use of a forage diet supplemented with fat and during subsequent turnout to pasture. ANIMALS 9 adult Standardbred mares (11 to 20 years old). Weight gain of horses was induced during 22 weeks by use of a forage diet supplemented with fat fed in gradually increasing amounts, followed by feeding of that fat-supplemented diet at 2.5 times the daily maintenance requirements. Horses were then turned out to pasture. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp method before and after weight gain and after 4 weeks at pasture. Body weight, body condition score, and cresty neck score as well as fasting and postprandial concentrations of plasma insulin, plasma glucose, serum triglyceride, and serum nonesterified fatty acids were measured during the study. Body weight typically increased by 10%, and body condition score (scale, 1 to 9) increased by > 1.5 from the start to the end of the weight-gain period. There was no difference in insulin sensitivity or metabolic clearance rate of insulin during the weight-gain period. Four weeks at pasture generally improved insulin sensitivity and metabolic clearance rate of insulin by 54% and 32%, respectively, but there was no change in body weight or body condition score. Findings indicated that dietary composition played a more important role than did short-term weight gain on alterations in insulin sensitivity of horses.

Effects of Growth Hormone on Diurnal Insulin Sensitivity in Normal and Type 2 Diabetic Patients and Animal Models

This review addresses the effects of growth hormone on diurnal insulin sensitivity in normal, patients with type 2 diabetes mellitus (T2DM) and animal models described in our previous studies. Results confirmed the presence of diurnal insulin sensitivity, or greater insulin sensitivity in the morning, in normal subjects. The exact cause of this circadian rhythm in plasma glucose levels in healthy subjects has not been established, and nocturnal surges in growth hormone secretion remain a possible explanation. Results showed that growth hormone is an important factor controlling the diurnal variation of glucose tolerance and insulin sensitivity in rats. Data from our previous study provided direct evidence that the role of growth hormone in regulating insulin sensitivity in healthy subjects may be related to changes in the metabolic clearance rate of insulin and the metabolism of non-esterified fatty acids. A different circadian rhythm for plasma glucose appears to be present in patients with T2DM with nadirs in the early evening and peaks in the early morning, indicating greater insulin sensitivity in the evening. As in normal subjects, the exact cause of these circadian rhythms in the plasma glucose levels of patients with T2DM provided direct evidence that the reduction in insulin sensitivity may be due to the nocturnal surge of growth hormone in the early morning hours.

Hyperinsulinemia in individuals with obesity: Role of insulin clearance.

ObjectiveSeveral studies have shown decreased insulin clearance rate (ICR) in individuals with obesity, but it remains unclear whether this is predominately due to obesity-associated insulin resistance (IR) or obesity itself. We aimed to clarify the complex interrelationship that exists between obesity, IR and ICR.MethodsHealthy volunteers (n = 277) had measurement of IR and ICR using the insulin suppression test (IST). IR was quantified by determining the steady-state plasma glucose (SSPG) during the IST. ICR was estimated by dividing the insulin infusion rate by the steady-state plasma insulin concentration. We performed our analysis by stratifying the experimental population into 4 dichotomous categories, varying in obesity and IR. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2, and IR was defined as SSPG ≥ 150 mg/dl.ResultsIndividuals with obesity had higher fasting insulin compared with individuals without obesity, regardless of IR. ICR was similar between individuals with and without obesity but was higher in IR individuals compared with insulin sensitive individuals. In multivariate analysis, both fasting insulin and SSPG were significantly associated with ICR. No significant relationships were observed between BMI and ICR.ConclusionsReduced ICR in obesity is secondary to IR, not excess adiposity.

Effect of long-term olanzapine treatment on meal-induced insulin sensitization and on gastrointestinal peptides in female Sprague-Dawley rats.

Meal-induced insulin sensitization (MIS), an endogenous adaptive mechanism is activated post-prandially. Reduced MIS leads to diabetes, but its activation improves insulin sensitivity. MIS is preserved to single olanzapine administration, therefore we aimed to investigate the chronic effect of olanzapine on fasted-state insulin sensitivity and on MIS in female Sprague-Dawley rats. Daily food and water intake, stool and urine production and body weight were determined. The MIS was characterized by a rapid insulin sensitivity test. Fasting hepatic and peripheral insulin sensitivity were determined by a hyperinsulinaemic euglycaemic glucose clamping supplemented with radiotracer technique. Fasted and post-prandial blood samples were obtained for plasma insulin, leptin, ghrelin, amylin, GLP-1, GIP, PYY and PP determination. Adiposity was characterized by weighing intra-abdominal and inguinal fat pads. Olanzapine caused hepatic insulin resistance and a reduced metabolic clearance rate of insulin, but the MIS retained its function. Body weight and adiposity were enhanced, but olanzapine failed to increase food intake. Fasting insulin and leptin were elevated and the post-prandial reduction in ghrelin level was inhibited by olanzapine.The MIS remained functionally intact after long-term olanzapine treatment. Altered insulin, leptin and ghrelin levels indicate olanzapine-induced metabolic derangements. Pharmacological activation of MIS could potentially be exploited to treat or prevent olanzapine-induced insulin resistance.

Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance.

Insulin resistance and compensatory hyperinsulinism are the predominant metabolic defects in polycystic ovary syndrome (PCOS). However, hyperinsulinism, as well as being compensatory, can also express a condition of reduced insulin clearance. Our aim was to evaluate the differences in insulin action and metabolism between women with PCOS (with normal glucose tolerance) and age- and BMI-matched women with prediabetes (without hyperandrogenism and ovulatory disorders). 22 women with PCOS and 21 age/BMI-matched women with prediabetes were subjected to a Hyperinsulinemic-euglycemic clamp and an Oral Glucose tolerance Test (OGTT). Insulin sensitivity was assessed by the glucose infusion rate during clamp (M value); insulin secretion by Insulinogenic index, Oral Disposition Index (DIo) and AUC(2h-insulin) during OGTT; and insulin clearance by the metabolic clearance rate of insulin (MCRI) during clamp. Women with PCOS showed significantly higher levels of AUC(2h-insulin) (p < 0.011), Insulinogenic Index (p < 0.001), DIo (p = 0.002) and significantly lower levels of AUC(2h-glucos)e (p = 0.001). No difference was found between the two groups regarding insulin sensitivity (M value). Lower levels of MCRI were found in women with PCOS [420 (IQR 227-588) vs. 743 (IQR 597-888) ml m(-2) min(-1): p < 0.001]. Furthermore, in the PCOS group, a strong independent inverse correlation was only observed between MCRI and AUC(2h-insulin) (PCOS: β:-0.878; p < 0.001; Prediabetes: β:-0.501; p = 0.019). Our study suggests that in normoglycemic women with PCOS there is peripheral insulin sensitivity similar to that of women with prediabetes. What sets PCOS apart is the hyperinsulinism, today still simplistically defined "compensatory"; actually this is mainly related to decreased insulin clearance whose specific causes and dynamics have yet to be clarified.

Effect of Growth Hormone on Dawn Phenomenon in Healthy Adults

The purpose of this study was to investigate the involvement of growth hormone in the diurnal variation of insulin sensitivity in healthy adults. Afternoon (16:00 hr) or night (23:00 hr) pretreatment with a subcutaneous injection of normal saline, human growth hormone to mimic the normal nocturnal rise in growth hormone, or octreotide to inhibit endogenous growth hormone secretion to create a state of relative nocturnal growth hormone deficiency, was given 16 hours before undergoing the modified insulin suppression test in healthy subjects. The morning and evening experiments were separated by an interval of at least 3 days. Thus, each subject was tested on six separate occasions arranged in a random order. A higher value of the steady-state plasma glucose (SSPG) is indicative of lower insulin sensitivity. Plasma glucose, serum insulin, insulin-like growth factor-1, nonesterified fatty acids (NEFA), and metabolic clearance rate of insulin (MCRI) were measured. In the normal saline and human growth hormone groups, SSPG levels were lower in the morning than in the evening. Evening SSPG levels, MCRI, and NEFA concentrations were higher in the participants treated with normal saline and growth hormone than in the octreotide group. Differences in SSPG levels between the morning and evening values were higher in the participants pretreated with normal saline and growth hormone than in those treated with octreotide. A diurnal variation in insulin sensitivity existed in healthy subjects. These results provided direct evidence that the role of growth hormone in regulating insulin sensitivity might be related to changes in the MCRI and the metabolism of NEFA in healthy subjects.

The Dawn Phenomenon: Variability in Occurrence May Cause Need for Change in Treatment Strategy

Schmidt et al ( 1. Schmidt M.I. Hadji-Georgopoulos A. Rendell M. Margolis S. Kowarski A. The dawn phenomenon, an early morning glucose rise: implications for diabetic intraday blood glucose variation. Diabetes Care. 1981; 4: 579-585 Crossref PubMed Scopus (147) Google Scholar ) defined “dawn phenomenon” as the night to morning elevation of blood glucose (BG) before and, to a larger extent, after breakfast in subjects with type 1 diabetes (T1D). A similar observation was made in type 2 diabetes (T2D) by Bolli et al in 1984 ( 2. Bolli G.B. Gerich J.E. The “dawn phenomenon”—a common occurrence in both non-insulin-dependent and insulin-dependent diabetes mellitus. N Engl J Med. 1984; 310: 746-750 Crossref PubMed Scopus (181) Google Scholar ). In normal, non-diabetic subjects ( 3. Kruszynska Y.T. Home P.D. Night-time metabolic changes in normal subjects in the absence of the dawn phenomenon. Diabete Metab. 1988; 14: 437-442 PubMed Google Scholar , 4. Schmidt M.I. Lin Q.X. Gwynne J.T. Jacobs S. Fasting early morning rise in peripheral insulin: evidence of the dawn phenomenon in nondiabetes. Diabetes Care. 1984; 7: 32-35 Crossref PubMed Scopus (59) Google Scholar , 5. Bolli G.B. De Feo P. De Cosmo S. et al. Demonstration of a dawn phenomenon in normal human volunteers. Diabetes. 1984; 33: 1150-1153 Crossref PubMed Google Scholar ), there is not a rise in glucose, due to a documented rise in insulin. Ever since the first description, the dawn phenomenon has been studied extensively. In T1D, the magnitude of BG elevation at dawn first reported was substantial, largely due to the decrease in plasma insulin concentration overnight ( 1. Schmidt M.I. Hadji-Georgopoulos A. Rendell M. Margolis S. Kowarski A. The dawn phenomenon, an early morning glucose rise: implications for diabetic intraday blood glucose variation. Diabetes Care. 1981; 4: 579-585 Crossref PubMed Scopus (147) Google Scholar ), commonly observed with evening administration of Lente or Neutral Protamine Hagedorn insulins ( 6. Owens D.R. Bolli G.B. Beyond the era of NPH insulin–long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application. Diabetes Technol Ther. 2008; 10: 333-349 Crossref PubMed Scopus (72) Google Scholar ). Even early studies with the biostator suggested a significant dawn phenomenon, due in part to an artifact caused by degradation of insulin over time in the biostator ( 7. Brennan J.R. Gebhart S.S. Blackard W.G. Pump-induced insulin aggregation. A problem with the Biostator. Diabetes. 1985; 34: 353-359 Crossref PubMed Scopus (60) Google Scholar ). More recent studies using continuous subcutaneous insulin infusion (CSII) or long-acting insulin analogs have suggested an increase of 25 to 50 mg/dL as the magnitude of the dawn phenomenon ( 8. Bending J.J. Pickup J.C. Collins A.C. Keen H. Rarity of a marked “dawn phenomenon” in diabetic subjects treated by continuous subcutaneous insulin infusion. Diabetes Care. 1985; 8: 28-33 Crossref PubMed Scopus (30) Google Scholar , 9. Perriello G. De Feo P. Torlone E. et al. The dawn phenomenon in type 1 (insulin-dependent) diabetes mellitus: magnitude, frequency, variability, and dependency on glucose counterregulation and insulin sensitivity. Diabetologia. 1991; 34: 21-28 Crossref PubMed Scopus (82) Google Scholar , 10. De Feo P. Perriello G. Ventura M.M. et al. Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon. Diabetologia. 1986; 29: 475-480 Crossref PubMed Scopus (53) Google Scholar ).

Diets High in Protein or Saturated Fat Do Not Affect Insulin Sensitivity or Plasma Concentrations of Lipids and Lipoproteins in Overweight and Obese Adults

Background:Previous human studies reported inconsistent effects of dietary protein and branched-chain amino acids (BCAAs) on insulin action and glucose metabolism. Similarly, it is unclear whether saturated fat (SF) intake influences these metabolic variables. Objective:The objective of this study was to test the effects of high [30% of energy (%E)] vs. moderate (20%E) intakes of protein (primarily whey) on insulin action and lipid and lipoprotein concentrations in the context of both high (15%E) and low (7%E) SF diets. Methods:The study was conducted as a randomized controlled trial in 158 overweight and obese men and women. After a 4-wk baseline diet [55%E carbohydrate, 15%E protein, 30%E fat (7%E SF)], participants were randomly assigned to 4 wk of either the baseline diet or 1 of 4 test diets containing 35%E carbohydrate and either 20%E or 30%E protein and either 7%E or 15%E SF. Frequently sampled i.v. glucose tolerance tests were administered after each dietary period. Results:Other than significantly higher fasting glucose concentrations for high vs. moderate protein intakes with a low-fat diet (difference ± SE: 0.47 ± 0.14 mmol/L; P = 0.001), there were no significant effects of dietary protein or SF on glucose metabolism, plasma insulin, or concentrations of lipids and lipoproteins. Changes in plasma BCAAs across all diets were negatively correlated with changes in the metabolic clearance rate of insulin (ρ = −0.18, P = 0.03) and positively correlated with changes in the acute insulin response to glucose (ρ = 0.15, P = 0.05). Conclusions:These findings suggest that short-term intake of BCAAs can influence insulin dynamics. However, in this group of overweight and obese individuals, neither high protein nor SF intake affected insulin sensitivity or plasma concentrations of lipids and lipoproteins. This trial was registered at clinicaltrials.gov as NCT00508937.

Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study.

OBJECTIVESalsalate treatment has been shown to improve glucose homeostasis, but the mechanism remains unclear. The aim of this study was to evaluate the effect of salsalate treatment on insulin action, secretion, and clearance rate in nondiabetic individuals with insulin resistance.RESEARCH DESIGN AND METHODSThis was a randomized (2:1), single-blind, placebo-controlled study of salsalate (3.5 g daily for 4 weeks) in nondiabetic individuals with insulin resistance. All individuals had measurement of glucose tolerance (75-g oral glucose tolerance test), steady-state plasma glucose (SSPG; insulin suppression test), and insulin secretion and clearance rate (graded-glucose infusion test) before and after treatment.RESULTSForty-one individuals were randomized to salsalate (n = 27) and placebo (n = 14). One individual from each group discontinued the study. Salsalate improved fasting (% mean change −7% [95% CI −10 to −14] vs. 1% [−3 to 5], P = 0.005) but not postprandial glucose concentration compared with placebo. Salsalate also lowered fasting triglyceride concentration (−25% [−34 to −15] vs. −6% [−26 to 14], P = 0.04). Salsalate had no effect on SSPG concentration or insulin secretion rate but significantly decreased insulin clearance rate compared with placebo (−23% [−30 to −16] vs. 3% [−10 to 15], P < 0.001). Salsalate was well tolerated, but four individuals needed a dose reduction due to symptoms.CONCLUSIONSSalsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentration. These improvements were associated with a decrease in insulin clearance rate without change in insulin action or insulin secretion.