First-phase Insulin Research Articles

Correlation between intrahepatic triglyceride content quantified by proton magnetic resonance spectroscopy and glucose metabolism

Objective: To investigate the correlation between intrahepatic triglyceride content (IHTC) and glucose metabolism in patients with non-alcoholic fatty liver disease (NAFLD) diagnosed by proton magnetic resonance spectroscopy (1H-MRS). Methods: A total of 239 subjects without diabetes mellitus were previously enrolled and underwent 1H-MRS scans. Anthropometric indexes including height, weight, waist and blood pressure, and laboratory findings as plasma glucose (PG), insulin (INS), C-peptide (CP), liver enzymes [alanine aminotransferase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT)] and lipid profiles were collected. According to IHTC levels, participants were divided into three groups: the non-NAFLD group (IHTC<5.56%), the mild NAFLD group (IHTC 5.56%-<33%), and the moderate and severe NAFLD group (IHTC ≥ 33%). The clinical characteristics of each group were analyzed, and the correlation between IHTC and glucose metabolism were assessed. Results: Compared with those in the non-NAFLD group, male proportion, waist, 120 min postprandial PG (PG120), CP, liver enzymes and total cholesterol (TC) levels were greater in the NAFLD group, whereas insulin sensitivity index-Cederholm (ISI-Cederholm) and high density lipoprotein cholesterol (HDL-C) levels were lower in the NAFLD groups. Subjects in the moderate and severe NAFLD group had higher levels of 120 min postprandial INS (INS120) and Stumvoll indexes, and lower ISI-Cederholm than those in the mild NAFLD group [80.37 (57.68, 112.70) mU/L vs.110.50(71.78, 172.80)mU/L, 1453(1178, 1798)vs.1737(1325, 2380), 358(297, 446) vs.441(318, 594), 2.27(2.01, 2.53) vs.2.06(1.81, 2.39), respectively, all P<0.05]. Correlation analyses showed that IHTC was significantly positively correlated with waist hip ratio (WHR), PG120, INS120, HOMA insulin resistance (HOMA-IR), Stumvoll 1st-insulin secretion, Stumvoll 2nd-insulin secretion, ALT, AST, GGT and TC (r=0.197, 0.274, 0.334, 0.162, 0.199, 0.211, 0.406, 0.361, 0.215, and 0.196, respectively, all P<0.05), and negatively correlated with ISI-Cederholm and HDL-C (r=-0.334, and-0.237, respectively, all P<0.05). Furthermore, a multiple linear stepwise regression analysis indicated that ISI-Cederholm (Standardized β =-0.298, P<0.001) and Stumvoll 1st insulin secretion (Standardized β = 0.164, P = 0.024) were independent factors of IHTC. Conclusions: Peripheral insulin resistance occurs in the early stage of NAFLD and becomes worse with the progression of the disease. IHTC was independently associated with insulin sensitivity and first-phase insulin secretion.

Impaired insulin exocytosis in chronic hepatitis C infection: contributory role of p38δ MAPK-protein kinase D-golgi complex axis.

Hepatitis C virus (HCV) infection and chronic hepatitis C (CHC) are associated with a measurable risk of insulin resistance (IR)/impaired glucose tolerance (IGT)/diabetes mellitus (DM). While loss of hepatic endocrine function contributes to liver cirrhosis in diabetic patients, onset and progression of IR/IGT to diabetes and exacerbation of incident hyperglycemia are ostensibly linked with chronic HCV infection. In this regard, the study by Chen J et al. appearing in Clinical Science (2020) (134(5) https://doi.org/10.1042/CS20190900) attempts to understand the mechanisms underlying the savaging effects of chronic HCV infection on insulin-producing pancreatic β-cells and hence diabetic onset. The study investigated the role of mitogen-activated protein kinase (MAPK) p38δ-protein kinase D (PKD)-golgi complex axis in impacting insulin exocytosis. It was inferred that an insulin secretory defect of pancreatic β-cells, owing to disrupted insulin exocytosis, to an extent explains β-cell dysfunction in HCV-infected or CHC milieu. HCV infection negatively regulates first-phase and second-phase insulin secretion by impinging on PKD-dependent insulin secretory granule fission at trans-golgi network and insulin secretory vesicle membrane fusion events. This commentary highlights the study in question, that deciphered the contribution of p38δ MAPK-PKD-golgi complex axis to β-cell dysfunction in CHC milieu. This pivotal axis proffers a formidable therapeutic opportunity for alleviation of double burden of glucose abnormalities/DM and CHC.

Former gestational diabetes: Mathematical modeling of intravenous glucose tolerance test for the assessment of insulin clearance and its determinants.

Women with a previous history of gestational diabetes mellitus (GDM) have increased risk of developing GDM in future pregnancies (i.e. recurrent GDM) and also Type 2 Diabetes (T2D). Insulin clearance represents one of the processes regulating glucose tolerance but has been scarcely investigated for its possible impairment in high-risk subjects. The aim of this study was to identify possible determinants of insulin clearance in women with a previous history of GDM. A detailed model-based analysis of a regular 3-hour, insulin-modified intravenous glucose tolerance test (IM-IVGTT) has been performed in women with a previous history of GDM (pGDM, n = 115) and in women who had a healthy pregnancy (CNT, n = 41) to assess total, first-phase and second-phase insulin clearance (ClINS-TOT, ClINS-FP and ClINS-SP) and other metabolic parameters (insulin sensitivity SI, glucose effectiveness SG, beta-cell function and disposition index DI). CLINS-SP was found increased in pGDM with respect to CNT and was found significantly inversely linearly correlated with SG (r = -0.20, p = 0.03, slope: -16.2, 95% CI -30.9 to -1.4, intercept: 1.1, 95% CI 0.7-1.4) and also with DI (r = -0.22, p = 0.02, slope: -10.0, 95% CI -18.5 to -1.6, intercept: 0.9, 95% CI 0.7-1.3). Disposition index, accounting for the combined contribution of insulin sensitivity and beta-cell function, and glucose effectiveness were identified as possible determinants of insulin clearance in women with a previous history of GDM. This may be of relevance for more accurate estimation and prevention of the risk for recurrent GDM and T2D.

Very high-protein and low-carbohydrate enteral nutrition formula and plasma glucose control in adults with type 2 diabetes mellitus: a randomized crossover trial

Background and objectivesStandard enteral nutrition (EN) formulas can worsen hyperglycemia in diabetic patients. We hypothesized that altering the proportion of macronutrients in a formula; increasing protein while decreasing carbohydrate concentrations would improve glycemic response. The objective of this study was to demonstrate that an EN formula containing a very high concentration of protein (in the form of whey peptides) and low concentration of carbohydrate provide better control of postprandial blood glucose relative to a very high-protein/higher-carbohydrate formula.Subjects and methodsThis was a randomized crossover clinical trial of 12 ambulatory adult subjects with type 2 diabetes. The primary outcome was glycemic response following a bolus of isocaloric amounts of two EN formulas; the secondary outcome was insulin response. Subjects were randomized to the experimental or the control formula, on two separate days, 5–7 days apart.ResultsMean blood glucose concentrations at 10–180 min post-infusion and mean area under the curve for glucose over 240 min post-infusion were significantly lower with the experimental formula than with the control formula (71.99 ± 595.18 and 452.62 ± 351.38, respectively; p = 0.025). There were no significant differences in the mean insulin concentrations over time, insulinogenic indices, and first-phase insulin measurements.ConclusionsAn EN formula containing high-protein and low-carbohydrate loads can significantly improve glucose control in subjects with type 2 diabetes in ambulatory settings as evidenced by observed improved glucose control without significant difference in insulin response.

Syntaxin-3 Binds and Regulates Both R- and L-Type Calcium Channels in Insulin-Secreting INS-1 832/13 Cells.

Syntaxin (Syn)-1A mediates exocytosis of predocked insulin-containing secretory granules (SGs) during first-phase glucose-stimulated insulin secretion (GSIS) in part via its interaction with plasma membrane (PM)-bound L-type voltage-gated calcium channels (Cav). In contrast, Syn-3 mediates exocytosis of newcomer SGs that accounts for second-phase GSIS. We now hypothesize that the newcomer SG Syn-3 preferentially binds and modulates R-type Cav opening, which was postulated to mediate second-phase GSIS. Indeed, glucose-stimulation of pancreatic islet β-cell line INS-1 induced a predominant increase in interaction between Syn-3 and Cavα1 pore-forming subunits of R-type Cav2.3 and to lesser extent L-type Cavs, while confirming the preferential interactions between Syn-1A with L-type (Cav1.2, Cav1.3) Cavs. Consistently, direct binding studies employing heterologous HEK cells confirmed that Syn-3 preferentially binds Cav2.3, whereas Syn-1A prefers L-type Cavs. We then used siRNA knockdown (KD) of Syn-3 in INS-1 to study the endogenous modulatory actions of Syn-3 on Cav channels. Syn-3 KD enhanced Ca2+ currents by 46% attributed mostly to R- and L-type Cavs. Interestingly, while the transmembrane domain of Syn-1A is the putative functional domain modulating Cav activity, it is the cytoplasmic domain of Syn-3 that appears to modulate Cav activity. We conclude that Syn-3 may mimic Syn-1A in the ability to bind and modulate Cavs, but preferring Cav2.3 to perhaps participate in triggering fusion of newcomer insulin SGs during second-phase GSIS.

Relationship between serum secreted Frizzled-related protein 4 and the pancreatic β cell function

Objective To investigate the relationship between serum secreted frizzled-related protein 4(SFRP4) and the first-phase of glucose-stimulated insulin secretion from pancreatic β cell under different glucose tolerance statuses. Methods Fifty-six patients with newly diagnosed type 2 diabetes mellitus(T2DM group), 52 patients with impaired glucose tolerance(IGT group), and 42 subjects with normal glucose tolerance(NGT group)underwent intravenous glucose tolerance test. Fasting serum SFRP4 and interleukin(IL)-1β were assayed by ELISA. Acute insulin response(AIR), the area under the curve of the first-phase(0-10 min)insulin secretion(AUC), glucose disposition index(GDI), homeostasis model assessment for β cell function index(HOMA-β), and insulin resistance index(HOMA-IR)were calculated. Results (1)The levels of SFRP4 and IL-1β in T2DM group and IGT group were significantly higher than that in NGT group[(184.38±61.34 or 141.64±40.46 or 95.46±20.13)ng/ml, P<0.01]. AIR, AUC, and GDI in T2DM group and IGT group were significantly lower than those in NGT group(P<0.01), and these results were more significantly reduced in T2DM group compared with those in IGT group.(2)SFRP4 was negatively correlated with AIR, AUC, GDI, HOMA-β(P<0.01), and positively correlated with fasting plasma glucose, 2 h plasma glucose after glucose loading, HbA1C, IL-1β, and high sensitive C-reactive protein(P<0.01). (3)Multiple stepwise regression analysis showed that AUC, HOMA-IR, and serum IL-1β level were independently associated with SFRP4. Conclusion The concentration of serum SFRP4 is closely correlated with the glycolipid metabolic disorder, the first-phase of glucose-stimulated insulin secretion, and chronic low-grade inflammation. SFRP4 may be involved in the mechanism of β cell dysfunction in type 2 diabetes mellitus. Key words: Secreted frizzled-related protein 4; β-cell function; Intravenous glucose tolerance test; Interleukin-1β; Diabetes mellitus, type 2

Measuring β-Cell Function Relative to Insulin Sensitivity in Youth

OBJECTIVETo compare β-cell function relative to insulin sensitivity, disposition index (DI), calculated from two clamps (2cDI, insulin sensitivity from the hyperinsulinemic-euglycemic clamp and first-phase insulin from the hyperglycemic clamp) with the DI calculated from the hyperglycemic clamp alone (hcDI).RESEARCH DESIGN AND METHODSComplete data from hyperglycemic and hyperinsulinemic-euglycemic clamps were available for 330 youth: 73 normal weight, 168 obese with normal glucose tolerance, 57 obese with impaired glucose tolerance, and 32 obese with type 2 diabetes. The correlation between hcDI and 2cDI and Bland-Altman analysis of agreement between the two were examined.RESULTSInsulin sensitivity and first-phase insulin from hcDI showed a hyperbolic relationship. The hcDI correlated significantly with 2cDI in the groups combined (r = 0.85, P < 0.001) and within each group separately (r ≥ 62, P < 0.001). Similar to 2cDI, hcDI showed a declining pattern of β-cell function across the glucose-tolerance groups. Overall, hcDI values were 27% greater than 2cDI, due to the hyperglycemic versus euglycemic conditions, reflected in a positive bias with Bland-Altman analysis.CONCLUSIONSβ-Cell function relative to insulin sensitivity could be accurately evaluated from a single hyperglycemic clamp, obviating the need for two separate clamp experiments, when lessening participant burden and reducing research costs are important considerations.

HbA1c Diagnostic Categories and β-Cell Function Relative to Insulin Sensitivity in Overweight/Obese Adolescents

OBJECTIVEThe recommended HbA1c diagnostic categories remain controversial and their utility in doubt in pediatrics. We hypothesized that alterations in the pathophysiologic mechanisms of type 2 diabetes may be evident in the American Diabetes Association recommended at-risk/prediabetes category (HbA1c 5.7 to <6.5%).RESEARCH DESIGN AND METHODSWe compared in vivo hepatic and peripheral insulin sensitivity by [6,6-2H2] glucose and a 3-h hyperinsulinemic-euglycemic clamp and β-cell function by a 2-h hyperglycemic clamp (∼225 mg/dL) in overweight/obese (BMI ≥85th percentile) adolescents with prediabetes (HbA1c 5.7 to <6.5%) (n = 160) to those with normal HbA1c (<5.7%) (n = 44). β-Cell function was expressed relative to insulin sensitivity (i.e., the disposition index = insulin sensitivity × first-phase insulin).RESULTSIn the prediabetes versus normal HbA1c category, fasting glucose, insulin, and oral glucose tolerance test (OGTT) area under the curve for glucose and insulin were significantly higher; hepatic and peripheral insulin sensitivity were lower; and β-cell function relative to insulin sensitivity was lower (366 ± 48 vs. 524 ± 25 mg/kg/min; P = 0.005). A total of 27% of youth in the normal HbA1c category and 41% in the prediabetes HbA1c category had dysglycemia (impaired fasting glucose and/or impaired glucose tolerance) by a 2-h OGTT.CONCLUSIONSOverweight/obese adolescents with HbA1c in the at-risk/prediabetes category demonstrate impaired β-cell function relative to insulin sensitivity, a metabolic marker for heightened risk of type 2 diabetes. Thus, HbA1c may be a suitable screening tool in large-scale epidemiological observational and/or interventional studies examining the progression or reversal of type 2 diabetes risk.

Progressive deterioration of β-cell function in obese youth with type 2 diabetes

In adults, type 2 diabetes (T2DM) is characterized with progressive deterioration in insulin secretion. Data are scanty in youth. We investigated prospectively the change in β-cell function and in insulin sensitivity in youth with T2DM.Six adolescents with T2DM [hemoglobin A1c (HbA1c) 6.6 ± 1.0%] underwent evaluation of hepatic glucose production (HGP; [6,6-²H₂] glucose), insulin-stimulated glucose disposal (Rd; hyperinsulinemic-euglycemic clamp), first- and second-phase insulin/C-peptide secretion (hyperglycemic clamp), body composition dual energy X-ray absorptiometry (DEXA), and abdominal adiposity (computed tomography) within 3 yr of the diagnosis of diabetes and after 12-16 months of follow-up.Weight, body mass index (37.1 ± 6.9), HbA1c (6.3 ± 0.7%), HGP (2.8 ± 1.2 mg/kg/min), and Rd (4.9 ± 3.4 mg/kg/min) did not change significantly from baseline. However, first-phase insulin and C-peptide declined (152.6 ± 261.2 vs. 75.9 ± 108.5 μU/mL, p = 0.028; 8.0 ± 6.3 vs. 5.9 ± 4.4 ng/mL, p = 0.048, respectively) with no significant change in second-phase insulin/C-peptide. The rate of decline in β-cell function was ∼20% per year.After a median duration of 20 months of diabetes, youth with T2DM manifest a rapid decline in β-cell function with no significant changes in peripheral or hepatic insulin sensitivity. Interventions to retard this deterioration in β-cell function should be investigated.

Type 2 diabetes in youth: are there racial differences in β-cell responsiveness relative to insulin sensitivity?

Non-diabetic African American (AA) youth have an upregulated insulin secretion relative to insulin sensitivity (IS) compared with their American White (AW) peers. We investigated if similar racial differences exist in youth with T2DM. Fourteen AAs and 14 AWs T2DM adolescents underwent evaluation of IS and clearance (hyperinsulinemic-euglycemic clamp), first- and second-phase insulin and C-peptide secretion (hyperglycemic clamp); body composition (DEXA); and abdominal adiposity (CT). AA and AW T2DM had similar HbA1c, diabetes duration, BMI, and % body fat, with lower visceral fat in AAs (p = 0.013). While insulin-stimulated glucose disposal was similar in AA and AW (7.5 ± 1.0 vs. 7.3 ± 0.9 mg/kg FFM/min), IS tended to be lower (2.5 ± 0.4 vs. 3.8 ± 0.6 mg/kg FFM/min per µU/mL, p = 0.081). First-phase insulin (175.7 ± 52.9 vs. 66.6 ± 10.8 µU/mL, p = 0.01) and second-phase insulin (236.2 ± 40.7 vs. 105.1 ± 17.9 µU/mL, p = 0.008), and first-phase C-peptide (8.2 ± 1.2 vs. 5.0 ± 0.3 ng/mL, p = 0.02) and second-phase C-peptide (10.8 ± 0.9 vs. 7.6 ± 0.6 ng/mL, p = 0.012) were higher in AA. β-Cell function relative to IS was higher in AA vs. AW (259.5 ± 35.3 vs. 168.8 ± 25.1 mg/kg FFM/min, p = 0.043). Racial differences in insulin secretion can be demonstrated with the clamp technique in obese adolescents with T2DM. Similar to non-diabetic youth, AA adolescents with T2DM compared with their AW counterparts have an upregulated β-cell function relative to IS, the reasons for which remain to be investigated.

Declining β-Cell Function Relative to Insulin Sensitivity With Escalating OGTT 2-h Glucose Concentrations in the Nondiabetic Through the Diabetic Range in Overweight Youth

OBJECTIVEOverweight in youth is associated with the risk of developing type 2 diabetes. We hypothesized that β-cell function relative to insulin sensitivity decreases with increasing 2-h glucose levels based on an oral glucose tolerance test (OGTT) in overweight youth.RESEARCH DESIGN AND METHODSA total of 147 overweight (BMI ≥85th percentile for age and sex) youth, aged 8 to <20 years, undertook three tests: 1) a 3-h hyperinsulinemic-euglycemic clamp; 2) a 2-h hyperglycemic clamp; and 3) a 2-h OGTT. Participants were categorically assigned to five groups according to their OGTT 2-h plasma glucose level, ranging from <120 to ≥200 mg/dL. β-Cell function relative to insulin sensitivity, assessed by clamp disposition index (DI) and oral disposition index (DIO), were compared among groups.RESULTSInsulin sensitivity, first-phase insulin, and DI declined significantly as 2-h glucose concentrations increased. The highest DI was found in youth with 2-h plasma glucose concentrations <120 mg/dL, with a significant decline of ~40% in those with glucose concentrations between 120 and <140 mg/dL, and an ~75% decline, the lowest DI, in youth with glucose concentrations ≥200 mg/dL. Data were similar with regard to the OGTT DIO.CONCLUSIONSThese data in overweight youth demonstrate that impairment in insulin secretion relative to insulin sensitivity is apparent even with normal glucose tolerance. Below the current cutoff of 140 mg/dL for impaired glucose tolerance, there is a >30% decline in β-cell function relative to insulin sensitivity. Against this back drop of metabolically heightened risk for type 2 diabetes, preventive measures should target the β-cell alongside insulin sensitization.

Insulin production and resistance in cystic fibrosis: effect of age, disease activity, and genotype.

To assess the major determinants of glucose tolerance between age, genotype, and clinical status in cystic fibrosis (CF) patients, and study if defects of insulin secretion and insulin sensitivity were associated with the onset of CF-related diabetes (CFRD). One hundred and nineteen patients, in stable clinical condition were studied. They were subdivided into 3 groups based on age, and 2 groups based on Schwachman-Kulczycki clinical score. All patients were genotyped, and subsequently divided into 3 groups. Ninety-four healthy normal-weight controls, comparable for sex and age were also studied. All subjects had baseline blood samples taken for glucose and insulin, C-peptide, and glycated hemoglobin. Homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose/insulin ratio (FGIR) were calculated as indices of IR and insulinogenic index as a marker of pancreatic β-cell function. All patients underwent an oral glucose tolerance test, and 57 underwent an IVGTT for the calculation of first-phase (FPIR) and acute insulin responses (AIR). The F508del homozygous patients had an increased chance of developing impaired glucose tolerance (IGT) and significantly lower FPIR, decreased HOMA-IR, and insulinogenic index. Heterozygote F508del patients had an increased chance of having normal glucose tolerance. HOMA-IR, FGIR, and insulinogenic index did not change with age or clinical score. HOMAIR correlated with FPIR. FPIR correlated positively with insulinogenic index. AIR correlated negatively with FGIR, and positively with C-reactive protein. In multiple linear regression analyses, glucose tolerance was related to the agegroup, and to the HOMA-IR and insulinogenic indexes. IGT and CFRD were related mainly to genotype, although, as expected, the prevalence increased with age. The data suggested a possible combined contribution of insulin deficiency, β-cell function, and reduced insulin sensitivity to the onset of CFRD; however, further studies are warranted to better elucidate this aspect.

From pre-diabetes to type 2 diabetes in obese youth: pathophysiological characteristics along the spectrum of glucose dysregulation.

OBJECTIVEImpaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are considered pre-diabetes states. There are limited data in pediatrics in regard to their pathophysiology. We investigated differences in insulin sensitivity and secretion among youth with IFG, IGT, and coexistent IFG/IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes.RESEARCH DESIGN AND METHODSA total of 24 obese adolescents with NGT, 13 with IFG, 29 with IGT, 11 with combined IFG/IGT, and 30 with type 2 diabetes underwent evaluation of hepatic glucose production ([6,6-2H2]glucose), insulin-stimulated glucose disposal (Rd, euglycemic clamp), first- and second-phase insulin secretion (hyperglycemic clamp), body composition (dual-energy X-ray absorptiometry), abdominal adiposity (computed tomography), and substrate oxidation (indirect calorimetry).RESULTSAdolescents with NGT, pre-diabetes, and type 2 diabetes had similar body composition and abdominal fat distribution. Rd was lower (P = 0.009) in adolescents with type 2 diabetes than in those with NGT. Compared with adolescents with NGT, first-phase insulin was lower in those with IFG, IGT, and IFG/IGT with further deterioration in those with type 2 diabetes (P < 0.001), and β-cell function relative to insulin sensitivity (glucose disposition index [GDI]) was also lower in those with IFG, IGT, and IFG/IGT (40, 47, and 47%, respectively), with a further decrease (80%) in those with type 2 diabetes (P < 0.001). GDI was the major determinant of fasting and 2-h glucose levels.CONCLUSIONSObese adolescents who show signs of glucose dysregulation, including abnormal fasting glucose, glucose intolerance or both, are more likely to have impaired insulin secretion rather than reduced insulin sensitivity. Given the impairment in insulin secretion, they are at high risk for progression to type 2 diabetes. Further deterioration in insulin sensitivity or secretion may enhance the risk for this progression.

First-Phase Insulin Secretion Has Limited Impact on Postprandial Glycemia in Subjects with Type 2 Diabetes: Correlations Between Hyperglycemic Glucose Clamp and Meal Test

Lack of first-phase insulin (INS) secretion is regarded as causative for high postprandial glucose excursions in subjects with type 2 diabetes. We aimed to determine the impact of early INS secretion on postprandial glycemia. Twenty subjects with type 2 diabetes (age 54 +/- 8 years, body mass index 28.7 +/- 2.7 kg/m(2) [mean +/- SD]) underwent a hyperglycemic glucose clamp and a meal test twice separated by a washout period of 4 weeks. Multiple regression analysis was used to identify determinants of postprandial glycemia. During hyperglycemic glucose clamps eight subjects showed a preserved first-phase INS secretion (P1+), whereas 12 subjects showed none (P1-). Both subject groups differed in fasting blood glucose (BG) (116 +/- 7 vs. 147 +/- 31 mg/dL, P = 0.011) and glycosylated hemoglobin (6.0 +/- 0.4 vs. 6.7 +/- 0.8, P = 0.041). Total INS secretory response during glucose clamps was higher in P1+ than P1- (INS-area under the concentration vs. time curve [AUC](0-120 min) 6.7 +/- 2.7 vs. 3.2 +/- 2.1 mU.min/mL; P = 0.006). During meal tests, however, INS-AUC(0-120 min) was similar between P1+ and P1-, whereas early INS secretion was still different (INS-AUC(0-60 min) 3.9 +/- 1.8 vs. 2.1 +/- 1.0 mU.min/mL; P = 0.031). Despite higher INS-AUC(0-60 min) in P1+, early postprandial BG was comparable between groups (BG-AUC(0-60 min) 1.5 +/- 0.5 vs. 1.6 +/- 0.6 g.min/dL; difference not significant). Multiple regression analyses showed no impact of first-phase INS secretion on postprandial glycemia, either in P1+ or in P1-. Nevertheless, in P1-, but not in P1+, postprandial glycemia was negatively correlated with INS sensitivity (R(2) = 0.83, P < 0.001). This study, correlating results of hyperglycemic glucose clamps with meal tests, shows that a preserved first-phase INS secretion has only a limited impact on postprandial glucose excursions in a group of subjects in early-stage type 2 diabetes.

Insulin Resistance, Hyperinsulinemia, and Energy Intake in Overweight Children

To examine the relationship between energy intake during a buffet meal and indexes of insulin dynamics in overweight children. Ninety-five nondiabetic, overweight (body mass index > or = 95th percentile) children (age 10.3 +/- 1.4 years) selected lunch from a 9835-kcal buffet eaten ad libitum after an overnight fast. The associations between energy intake and measures of insulin dynamics, in the postabsorptive state and during a 2-hour hyperglycemic clamp, were determined. Covariates in the statistical model included race, sex, skeletal age, fat-free mass, fat mass, socioeconomic status, and number of foods in the buffet rated as acceptable. Energy intake was positively associated with the fasting homeostasis model assessment for insulin resistance index (beta = 0.24, P = .042), fasting insulin/glucose ratio (beta = 0.24, P = .044), first-phase insulin (beta = 0.23, P = .032), and first-phase C-peptide (beta = 0.21, P = .046); energy intake was negatively associated with clamp-derived insulin sensitivity (beta = -0.29, P = .042). Each 10% decrease in clamp-derived insulin sensitivity predicted a 27-kcal greater energy intake. Insulin resistance and hyperinsulinemia are associated with greater energy intake after an overnight fast in overweight children. These associations suggest mechanisms whereby insulin resistance may contribute to excessive weight gain in children.

Can stevioside in combination with a soy-based dietary supplement be a new useful treatment of type 2 diabetes? An in vivo study in the diabetic goto-kakizaki rat.

The diterpene glycoside stevioside (SVS) and soy bean protein isolate have both been shown to have beneficial effects in diabetes treatment. As they each show different benefits we investigated whether the combination of both substances shows an improvement in the treatment of diabetes in Goto-Kakizaki (GK) rats. Over the course of 4 wk, the rats were fed with the following four test diets (n = 12 per group): 1. Standard carbohydrate-rich laboratory diet (chow), 2. chow + SVS (0.03 g/kg BW/day), 3. 80% SPI + 20% chow and 4. 80% SPI + 20 % chow + SVS (0.03 g/kg BW/day). At the end of the course conscious rats underwent an intra-arterial glucose tolerance test (IAGTT) (2.0 g glucose/kg BW). Compared to normal chow diet, stevioside in combination with SPI shows the following beneficial effects in GK rats with mild type 2 diabetes: 1. a 56% reduction in plasma glucose (p < 0.001), 2. a 118% increase in first-phase insulin (p < 0.005), 3. a 20% reduction in glucagons (p < 0.05), 4. a 28% reduction in total cholesterol (p < 0.001), 5. a 13% reduction in FFA (p < 0.01), 6. a 49% reduction in TG (p < 0.001) and 7. a 11% reduction in the systolic blood pressure (p < 0.001). In conclusion, the combination of stevioside and SPI has synergistic positive effects on the characteristic features of the metabolic syndrome, i.e. hyperglycemia, hypertension and dyslipidemia.

Dietary Restriction and Beta-Cell Sensitivity to Glucose in Adult Male Rhesus Monkeys

We examined the effects of dietary restriction (DR) and age on ss-cell function and peripheral insulin sensitivity in rhesus monkeys. A semipurified diet was provided either ad libitum for approximately 8 hours/day to controls (C) or as approximately 70% of baseline intake to restricted (R) animals for 10 years. The minimal model of C-peptide secretion and kinetics and the labeled 2-compartment minimal model of glucose kinetics were identified using plasma glucose, C-peptide, and insulin concentrations during an intravenous glucose tolerance test. R monkeys had less body fat, lower basal ss-cell sensitivity to glucose (Ø(b)), greater insulin sensitivity, and lower first-phase plasma insulin response. DR did not significantly affect first-phase and second-phase ss-cell sensitivity to glucose. Indices of body fatness were highly predictive of the effect of DR on Ø(b), fasting insulin concentration and insulin responses to glucose. Enhanced peripheral insulin sensitivity among R monkeys was strongly correlated with lower Ø(b).

Hyperinsulinemia in african-american children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity.

African-American (AA) children are hyperinsulinemic and insulin resistant compared with American White (AW) children. This study investigated 1) whether AA/AW differences in insulinemia are associated with differences in insulin clearance; 2) whether dietary patterns, mainly carbohydrate and fat intake, play a role; and 3) whether the quantitative relationship between insulin sensitivity and secretion is similar between AA and AW children. Forty-four prepubertal children (22 AA and 22 AW) with comparable body composition and visceral adiposity were studied. All underwent a 3-h hyperinsulinemic (40 mU x m(-2) x min(-1))-euglycemic clamp to calculate insulin sensitivity and insulin clearance and a 2-h hyperglycemic clamp (12.5 mmol/l) to assess first- and second-phase insulin responses. Twenty-four-hour food recalls were analyzed for macronutrient intake. Insulin clearance (19.5 +/- 0.7 vs. 22.9 +/- 1.1 ml x min(-1) x kg(-1) fat-free mass [FFM]; P = 0.011) and insulin sensitivity were lower in AA versus AW children (14.8 +/- 1.0 vs. 18.9 +/- 1.4 micro mol x min(-1) x kg(-1) FFM; P = 0.021). Both insulin clearance and insulin sensitivity correlated inversely with dietary fat/carbohydrate ratio, which was higher in AA than in white children. Fasting C-peptide and insulin were higher in AA children with no difference in proinsulin levels. First- and second-phase insulin concentrations and glucose disposition index (insulin sensitivity x first-phase insulin) were higher in AA than in white children (12.8 +/- 2.1 vs. 7.2 +/- 0.6 micro mol. min(-1) x kg(-1) FFM; P = 0.019). In conclusion, the hyperinsulinemia observed in AA children is due to both lower insulin clearance and higher insulin secretion compared with their white peers. The quantitative relationship between insulin secretion and sensitivity is upregulated in AA children. This suggests that increased insulin secretion in AA children is not merely a compensatory response to lower insulin sensitivity. Dietary factors may have a role. Additional studies are needed to determine whether metabolic/nutritional factors, possibly mediated through free fatty acids, may play a role in the hyperinsulinism observed in AA children.

Physiological consequences of phasic insulin release in the normal animal.

The dose-response relationship between the hepatic sinusoidal insulin level and glucose production by the liver is such that a half-maximally effective concentration is at or slightly below the hormone levels seen basally after an overnight fast. In the normal individual, the direct effect of the hormone on the hepatocyte is far more important in restraining glucose production than its indirect effect mediated via a suppression of lipolysis. Because insulin regulates the liver in a direct fashion, its effect occurs within several minutes. Thus, the speed with which insulin works and the sensitivity of the liver to it predict that first-phase insulin release should have a significant effect in quickly suppressing hepatic glucose production. On the other hand, nonhepatic tissues are much less sensitive to insulin and respond slowly as a result of the need for insulin to cross the endothelial barrier. As a result, first-phase insulin is unlikely to significantly alter peripheral glucose disposal. Simulation studies in humans and dogs in which the effects of first-phase insulin were simulated confirmed the aforementioned predictions. In addition, they confirmed the ability of second-phase insulin release to have significant effects on both glucose production and utilization.

Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).

Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of beta-cell function referred to as maturity-onset diabetes of the young 4. IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp on seven heterozygous members (NM) and eight normal genotype members (NN). During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol x kg(-1) x min(-1)). Fasting plasma glucose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P < 0.05). Fasting insulin levels were similar in both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group. At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion. Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects. A sharp decline occurred in the dose-response curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of beta-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of beta-cell dysfunction.