Insulin Secretion In Obese Subjects Research Articles

Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function.

To examine the relationship between plasma glucagon levels and insulin sensitivity and insulin secretion in obese subjects. Suppression of plasma glucagon was examined in 275 obese Hispanic Americans with varying glucose tolerance. All subjects received a 2-hour oral glucose tolerance test (OGTT) and a subset (n = 90) had euglycemic hyperinsulinemic clamp. During OGTT, we quantitated suppression of plasma glucagon concentration, Matsuda index of insulin sensitivity, and insulin secretion/insulin resistance (disposition) index. Plasma glucagon suppression was compared between quartiles of insulin sensitivity and beta-cell function. Fasting plasma glucagon levels were similar in obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D), but the fasting glucagon/insulin ratio decreased progressively from NGT to prediabetes to T2D (9.28 ± 0.66 vs 6.84 ± 0.44 vs 5.84 ± 0.43; P < 0.001). Fasting and 2-hour plasma glucagon levels during OGTT progressively increased and correlated positively with severity of insulin resistance (both Matsuda index and euglycemic hyperinsulinemic clamp). The fasting glucagon/insulin ratio declined with worsening insulin sensitivity and beta-cell function, and correlated with whole-body insulin sensitivity (Matsuda index, r = 0.81; P < 0.001) and beta-cell function (r = 0.35; P < 0.001). The glucagon/insulin ratio also correlated and with beta-cell function during OGTT at 60 and 120 minutes (r = -0.47; P < 0.001 and r = -0.32; P < 0.001). Insulin-mediated suppression of glucagon secretion in obese subjects is impaired with increasing severity of glucose intolerance and parallels the severity of insulin resistance and beta-cell dysfunction.

2002-P: Waist-Hip Ratio: A Better Obesity Measure Index Represents Insulin Secretion among Obese Women with Different Glucose Metabolism Status

Objective: To investigate the association of simple obesity measures (BMI, WC and WHR) with insulin secretion in obese subjects with normal glucose metabolism (NGM), prediabetes, and T2DM. Research Design and Methods: 848 obese patients were recruited and divided into three groups (428 NGM, 248 prediabetes, and 172 T2DM). BMI, WC, and WHR were obtained. Insulin secretion was described by three beta cell function indices (HOMA-β, ΔI30/ΔG30 and AUCI60-120). Pearson correlation analysis and multiple linear regression analysis were used. In addition, 284 subjects estimated their body fat by dual x-ray absorptiometry. The joint relationship between obesity measures, body fat and insulin secretion were studied. Results: As glucose metabolism spectrum changed from NGM to prediabetes and to T2DM, the correlation between WHR and insulin secretion declined (from r=0.286**, r=0.081, r=0.2** to r=-0.012, r=-0.072, r=-0.074 and to r=-0.173*, r=-0.175*, r=-0.171*; *P &amp;lt; 0.05, **P &amp;lt; 0.01). In contrast, BMI and WC showed a consistent association with insulin secretion (r&amp;gt;0). Similar relevant reversal was only found in female subjects. There were significant interactions of WHR and glucose status on insulin secretion in female subjects, in this adjusted model, WHR was associated with higher insulin secretion in NGM group (1.19±0.23**, 0.58±0.32, 0.82±0.26**) and lower in T2DM group (-0.77±0.34*, -1.78±0.47**, -1.36±0.39), not prediabetes (0.15±0.27, 0.08±0.38, 0.28±0.31). Adding HOMA-IR to the core model can increase the inverse associations. Elevated limb fat to trunk fat ratio had significantly lower insulin secretion levels, and the relationship between this fat ratio and WHR was considerably strong in female. Conclusions: WHR and insulin secretion relationship is dependent on glucose status among obese women. As diabetes developed, higher WHR revealed lower insulin secretion, which may be attributed to more fat distributed in extremities. Disclosure J. Wu: None. B. Wang: None.

Differences in insulin resistance and pancreatic B‐cell function in obese subjects with isolated impaired glucose tolerance and isolated impaired fasting glucose

To investigate changes in insulin action and insulin secretion in obese subjects with different categories of impaired glucose regulation (IGR): impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and combined IFG/IGT (CGI). A total of 222 subjects underwent an oral glucose tolerance test and a frequently sampled intravenous glucose tolerance test (FSIGTT); 100 had normal glucose tolerance (subdivided into 32 lean NGT, 68 obese NGT), and 122 were obese with IGR (82 IGT, 14 IFG and 26 CGI). The insulin sensitivity index (S(I)) was assessed by Bergman's minimal model method with FSIGTT; insulin secretion was determined by acute insulin response to glucose (AIRg). The disposition index (DI), the product of AIRg and S(I), was used to determine whether AIRg was adequate to compensate for insulin resistance. S(I) was similar in NGT and IGR obese subgroups. AIRg was significantly increased in obese NGT as compared with lean NGT, significantly reduced in IGT, and further reduced in IFG and CGI subjects as compared with obese NGT subgroups. DI was reduced in NGT obese individuals. Within the obese IGR subgroups, IFG and CGI subjects had even lower DI value than IGT subjects. Obese Chinese subjects with IGR have a similar degree of insulin resistance but differ in insulin secretion. Subjects with IFG and CGI have a more prominent deficiency in insulin secretion than subjects with IGT.

Restoration of Acute Insulin Response in T2DM Subjects 1 Month After Biliopancreatic Diversion

Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes. Twenty-one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA-IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([DeltaI5/DeltaG5]/HOMA-IR). Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 +/- 29.5 vs. 644.9 +/- 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 +/- 0.5 vs. 17.6 +/- 3.9 1/mmol(2), P < 0.001). One month following BPD, in both groups BW was reduced (by approximately 11%), but all subjects were still severely obese; HOMA-IR and leptin decreased significanlty, while high-molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non-diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 +/- 29.5 to 273.8 +/- 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia. BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.

Impact of Family History of Diabetes and Ethnicity on β-Cell Function in Obese, Glucose-Tolerant Individuals

The increased insulin secretion in response to reduced insulin sensitivity (SI) is heritable, but whether the genetic predisposition is restricted to members of high-risk Caucasian families is unknown. Furthermore, the relative importance of insulin resistance and defective beta-cell compensation in the increased prevalence of type 2 diabetes (T2DM) in African-American compared with Caucasian individuals is uncertain. We tested whether obese individuals with a family history of T2DM have decreased beta-cell compensation compared with obese controls without a family history of T2DM. In addition, we compared S(I) and insulin secretion measures in African-American and Caucasian individuals. SI, acute insulin response to iv glucose (AIRg), maximally potentiated insulin response to arginine (AIRmax), and disposition indexes (DIs) (DI = SI * AIRg; DImax = SI * AIRmax) were compared among nondiabetic Caucasian and African-American individuals with and without a family history of diabetes. This study was performed in an Ambulatory General Clinical Research Center. SUBJECTS were healthy, nondiabetic individuals with or without a family history of T2DM. There were no interventions. Comparison of SI, AIRg, AIRmax, DI, and DImax between Caucasians and African-Americans with or without a strong family history of T2DM were made. Obese subjects did not differ in SI, AIRg, or DI by family history of diabetes. African-Americans had 8% lower SI (P < 0.001), but 68% higher AIRg (P < 0.001) and 46% higher DI (P = 0.001) than age, gender, body mass index-matched Caucasian individuals. However, African-Americans had lower DImax compared with Caucasians. We found no reduction in insulin secretion in obese subjects with a family history of T2DM compared with controls, but in general, African-Americans were more insulin resistant and had lower maximal beta-cell response (DImax). The paradoxical increased DI could be explained by the reduced hepatic insulin extraction.

Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.

The pattern of endogenous insulin secretion over a 24-h period, which included three mixed meals, was evaluated in 14 normal volunteers and 15 obese subjects. Insulin secretory rates were calculated from plasma C-peptide levels using individually derived C-peptide kinetic parameters and a validated open two-compartment model of peripheral C-peptide kinetics. Insulin secretion rates were consistently elevated in the obese subjects under basal conditions (11.6 +/- 1.2 vs. 5.4 +/- 0.5 nmol/h) and in the 4 h after breakfast (139 +/- 15 vs. 63 +/- 5 nmol/4 h, P less than 0.001), lunch (152 +/- 16 vs. 67 +/- 5 nmol/4 h, P less than 0.001), and dinner (145 +/- 18 vs. 65 +/- 6 nmol/4 h, P less than 0.001). In the normal subjects, basal insulin secretion represented 50 +/- 2.1% of total 24-h insulin production, insulin secretion returned to baseline between meals, and equal quantities of insulin were secreted in the 4 h after breakfast, lunch, and dinner, despite the fact that subjects consumed half the number of calories at breakfast compared to lunch and dinner. Overall glucose responses were also similar after the three meals. In contrast, the pattern of insulin secretion in obese subjects was largely normal, albeit set at a higher level. However, the insulin secretion rate after meals did not return to baseline, and the secretion rate immediately before lunch (350.5 +/- 81.9 pmol/min) and dinner (373.6 +/- 64.8 pmol/min) was considerably higher than the secretion rate immediately before breakfast (175.5 +/- 18.5 pmol/min). In these overweight subjects, the glucose response after lunch was lower than after dinner. Analysis of individual 24-h insulin secretory profiles in the normal subjects revealed that insulin secretion was pulsatile. On average 11.1 +/- 0.5 pulses were produced in each 24-h period. The most prevalent temporal distribution of postmeal secretory pulses was two pulses after breakfast and three pulses after both lunch and dinner. Insulin secretion was also pulsatile during the period without meal stimuli: 3.9 +/- 0.3 pulses occurred during the period of overnight sampling and in the 3-h period before ingestion of the breakfast meal. In the obese subjects, the number and timing of secretory pulses was similar to those of normal volunteers, although the amplitude of the pulses was significantly greater. In both groups of subjects, greater than 80% of insulin pulses were concomitant with a pulse in glucose concentration in the postmeal period. The concomitancy rate was significantly lower in the interval without the meal stimuli, averaging 47% in both groups. Thus in obesity, although hypersecretion of insulin can be documented, the temporal pattern of secretion i s largely unaltered, which suggests that the functioning beta cell mass is enhance, but normal regulatory mechanisms influencing secretion are still operative.

Effect of diphenylhydantoin on patterns of insulin secretion in obese subjects.

The effect of short-term treatment with diphenylhydantoin (DPH) on the insulin secretion patterns during OGTT and on the daily insulin profile was studied in obese patients. DPH treatment for 3 days with a dose of 300 mg/die (100 mg, 3 times daily) significantly decreased the insulin release after glucose ingestion, but did not alter the basal insulin level. No effect on the fasting glucose concentration as well as on the glucose profiles during OGTT was observed after short-term DPH treatment. A smaller decrease of plasma free fatty acid concentration during OGTT performed after DPH administration confirmed the inhibitory effect of the drug on insulin release. Short-term DPH treatment was also shown to decrease markedly the postpradial insulin release in obese patients. No difference was noted between plasma 11-OHCS and serum HGH concentrations during OGTT before and after DPH treatment. The possible therapeutic role of DPH in obesity is discussed.