Effect of somatostatin (SRIF) on plasma glucose and insulin response to glucagon in liver cirrhosis

Summary The present study was performed in order to evaluate the plasma glucose pattern in cirrhotic patients who, in the course of a continuous somatostatin infusion (500 μg/h), were given pulses of glucagon (1 mg i.v.). In normal as well as in cirrhotic subjects somatostatin infusion provoked a marked reduction of the IRI plasma level and this was uninfluenced by subsequent glucagon administration. The rise in plasma glucose level in response to i.v. glucagon administration during somatostatin infusion was less marked in cirrhotics compared to normal subjects. This can be attributed to a variety of factors such as reduced number of liver cells or quantitative or qualitative changes of the liver cell glucagon receptors. Glucagon does not seem to contribute to the pathogenesis of carbohydrate intolerance in liver cirrhosis.     

Glucose intolerance in uremia (A- and B-cell function during conservative and dialytic management)

Summary Glucose tolerance and insulin and glucagon secretion were investigated in two groups of uremic patients, respectively on conservative and hemodialytic treatment. For this purpose, a glucose infusion was performed in the fasting state. Glucose intolerance was observed in uremic patients; hemodialysis improved, but did not normalize the glucose disposal. In uremic patients both on conservative and dialytic treatment plasma insulin and glucagon levels were higher than in the control group; the pattern of glucagon suppression was well maintained. The data obtained suggest that glucose intolerance in uremia is related mainly to peripheral insulin resistance and is not due to hyperglucagonemia.     

脑室灌注肾上腺髓质素对大鼠血糖和血糖调节激素的影响

灌注脑室以不同溶剂配制的肾上腺髓质素(AM),观察并比较它们对血糖及血糖调节激素的影响.结果表明:(1)中枢给以生理盐水配制的AM,可使血浆胰岛素、C 肽明显升高,胰升糖素、血糖浓度降低.(2)用30%葡萄糖配制AM与单纯灌注糖溶液相比,AM可使血浆胰岛素、C肽明显升高,胰升糖素明显降低,血糖浓度则无差异.说明AM参与中枢神经系统对胰岛分泌激素的调节.     

Fasting tests of insulin secretion and sensitivity predict future prediabetes in Japanese with normal glucose tolerance

Aims/Introduction:  Reduced insulin sensitivity and secretion are important in the pathogenesis of type 2 diabetes. Their relationships to prediabetes, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have been previously studied with the oral glucose tolerance test (OGTT). We investigated whether or not baseline measures of insulin secretion and sensitivity obtained from fasting blood specimens were related to the development of prediabetes and how these measures compared with those based on the OGTT.Materials and Methods:  In 152 Japanese subjects with normal glucose tolerance, we measured baseline plasma glucose and insulin after an overnight fast and during a 75 g OGTT, insulin resistance index (homeostasis model assessment [HOMA‐IR]), and insulin secretion (insulinogenic index [30 min insulin − fasting insulin] ÷ [30 min glucose − fasting glucose] or HOMA‐β).Results:  At a 5–6 year (mean 5.7 years) follow‐up examination, we confirmed 36 cases of prediabetes. After adjusting for age, sex, family history of diabetes, body mass index, and 2‐h plasma glucose, the odds ratio comparing the lowest tertile (≤0.82) of insulinogenic index with the highest tertile (≥1.43) was 6.98 (95% confidence interval, 1.96–24.85) and was 10.72 (2.08–55.3) comparing the lowest tertile (≤76.3) of HOMA‐β with the highest tertile (≥122.1), whereas the respective odds ratios of HOMA‐IR were 3.74 (1.03–13.57) and 10.89 (1.93–61.41) comparing the highest tertile (≥1.95) with the lowest tertile (≤1.25).Conclusions:  Lower insulin secretion and sensitivity are independent risk factors for prediabetes. Clinically practical identification of those at risk for prediabetes is obtainable from HOMA‐β and HOMA‐IR, both of which are measured in fasting state. (J Diabetes Invest, doi: 10.1111.j.2040‐1124.2010.00041.x, 2010)     

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Aims/hypothesis The study evaluated whether glucagon secretion is regulated by changes in insulin sensitivity under normal conditions. Materials and methods A total of 155 healthy women with NGT (aged 53–70 years) underwent a glucose-dependent arginine-stimulation test for evaluation of glucagon secretion. Arginine (5 g) was injected i.v. under fasting conditions (plasma glucose 4.8±0.1 mmol/l) and after raising blood glucose concentrations to 14.8±0.1 and 29.8±0.2 mmol/l. The acute glucagon response (AGR) to arginine during the three glucose levels (AGR₁, AGR₂, AGR₃) was estimated, as was the suppression of baseline glucagon by the increased glucose. All women also underwent a 2-h euglycaemic–hyperinsulinaemic clamp study for estimation of insulin sensitivity. Results Insulin sensitivity was normally distributed, with a mean of 73.2±29.3 (SD) nmol glucose kg⁻¹ min⁻¹/pmol insulin l⁻¹. When relating the variables obtained from the arginine test to insulin sensitivity, insulin resistance was associated with increased AGR and with increased suppression of glucagon levels by glucose. For example, the regression between insulin sensitivity and AGR₂ was r=−0.38 (p<0.001) and between insulin sensitivity and suppression of glucagon levels by 14.8 mmol/l glucose r=0.36 (p<0.001). Insulin sensitivity also correlated negatively with insulin secretion; multivariate analysis revealed that changes in insulin sensitivity and insulin secretion were independently related to changes in glucagon secretion. Conclusions/interpretation The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of glucagon levels by glucose. Hence, not only the islet beta cells but also the alpha cells seem to undergo compensatory changes during the development of insulin resistance.     

Insulin resistance and plasma glucose tolerance abnormalities in Nigerians with chronic liver disease

AimsGlucose tolerance abnormalities are frequently observed in patients with chronic liver disease (CLD). Insulin resistance (IR) has been suggested to be a major factor responsible for these abnormalities in CLD. However studies relating IR with severity of CLD are scarce in Nigeria. This study assessed insulin resistance and glucose tolerance abnormalities in CLD and their relationship with the severity of CLD in a tertiary hospital in South-West, Nigeria.MethodsThis cross sectional study involved 100 subjects with CLD. Ethical clearance was obtained and informed consent was granted by participants. Participants were interviewed using a structured proforma; physical examination and relevant investigations were performed. Insulin resistance was measured using the homeostasis model assessment (HOMA-IR) Data was analysed using Statistical Package for Social Sciences version 20.0 and p value of <0.05 was considered significant.ResultsMean age of the study participants was 51.9 ± 11.9 years, and mean duration of CLD was 15.9 ± 5.8 months. Glucose tolerance abnormalities were present in 66 subjects (66%) and increased from 16.1% in Child Pugh's class A to 90.0% in class C.HOMA-IR positively correlated with age, body mass index, serum blood glucose, duration and severity of CLD. Increasing age, presence of hepatocellular carcinoma, Child Pugh's class B and class C were associated with glucose tolerance abnormalities.ConclusionGlucose tolerance abnormalities and insulin resistance were highly prevalent among chronic liver disease subjects studied and seemed to parallel the severity of CLD, determined by the Child Pugh's score.     

Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet

Aims/hypothesis Increased glucagon secretion predicts deterioration of glucose tolerance, and high glucagon levels contribute to hyperglycaemia in type 2 diabetes. Inhibition of glucagon action may therefore be a potential novel target to reduce hyperglycaemia. Here, we investigated whether chronic treatment with a glucagon receptor antagonist (GRA) improves islet dysfunction in female mice on a high-fat diet (HFD). Materials and methods After 8 weeks of HFD, mice were treated with a small molecule GRA (300 mg/kg, gavage once daily) for up to 30 days. Insulin secretion was studied after oral and intravenous administration of glucose and glucagon secretion after intravenous arginine. Islet morphology was examined and insulin secretion and glucose oxidation were measured in isolated islets. Results Fasting plasma glucose levels were reduced by GRA (6.0 ± 0.2 vs 7.4 ± 0.5 mmol/l; p = 0.017). The acute insulin response to intravenous glucose was augmented (1,300 ± 110 vs 790 ± 64 pmol/l; p < 0.001). The early insulin response to oral glucose was reduced in mice on HFD + GRA (1,890 ± 160 vs 3,040 ± 420 pmol/l; p = 0.012), but glucose excursions were improved. Intravenous arginine significantly increased the acute glucagon response (129 ± 12 vs 36 ± 6 ng/l in controls; p < 0.01), notably without affecting plasma glucose. GRA caused a modest increase in alpha cell mass, while beta cell mass was similar to that in mice on HFD + vehicle. Isolated islets displayed improved glucose-stimulated insulin secretion after GRA treatment (0.061 ± 0.007 vs 0.030 ± 0.004 pmol islet⁻¹ h⁻¹ at 16.7 mmol/l glucose; p < 0.001), without affecting islet glucose oxidation. Conclusions/interpretation Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion, suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes.     

DPP‐4 inhibition and islet function

During recent years, dipeptidyl peptidase‐4 (DPP‐4) inhibition has been included in the clinical management of type 2 diabetes, both as monotherapy and as add‐on to several other therapies. DPP‐4 inhibition prevents the inactivation of the incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1). This results in stimulation of insulin secretion and inhibition of glucagon secretion, and there is also a potential β‐cell preservation effect, as judged from rodent studies; that is, it might target the key islet dysfunction in the disease. In type 2 diabetes. This reduces 24‐h glucose levels and reduces HbA_1c by ≈ 0.8–1.1% from baseline levels of 7.7–8.5%. DPP‐4 inhibition is safe, with a very low risk for adverse events including hypoglycemia, and it prevents weight gain. The present review summarizes the studies on the influence of DPP‐4 inhibition on islet function. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00184.x, 2012)     

Feedback inhibition of insulin and glucagon secretion by insulin is altered in abdominal obesity with normal or impaired glucose tolerance

We investigated the feedback inhibition of insulin and glucagon secretion during euglycemic-hyperinsulinemic clamp at about 350 pmol/l in 16 patients with abdominal obesity [8 with normal glucose tolerance (oNGT), 8 with impaired glucose tolerance (oIGT)] and 8 normal-weight subjects matched for age, sex and blood pressure. In oNGT and oIGT, fasting plasma C-peptide levels were twice those in the controls (962±51 and 915±85 vs 439±28 pmol/l,P<0.001) and their suppression was lower than in the controls, both in absolute terms (155±19 and 185±17 vs 274±18 pmol/l,P<0.001) and as a percentage decline from basal levels (16±2% and 21±2% vs 63±2%,P<0.001). Fasting plasma glucagon levels were similar in the patients and in the controls, but were less suppressed during clamp in oNGT and oIGT, both in absolute terms (7.0±0.9 and 5.6±0.6 vs 13.2±1.2 pmol/l,P<0.001) and as a percentage change from basal levels (23±3% and 19±2% vs 44±4%,P<0.001). These results suggest that the insulin feedback on B and A cells is impaired in abdominal obesity, and that this defect is of similar degree in oNGT and oIGT. These alterations could be implicated in the pathogenesis of hyperinsulinemia in obesity.     

The effects of epinephrine on islet hormone secretion in the dog

Summary We investigated the direct effects of physiological levels of epinephrine on the basal and arginine-stimulated secretion of insulin, glucagon, and somatostatin from the in situ pancreas in halothane-anaesthetized dogs. An IV infusion of 20 ng/kg/min of epinephrine increased plasma epinephrine levels to 918±103 pg/ml (P<0.001), and increased the baseline pancreatic output of insulin (P<0.05), glucagon (P<0.05) and somatostatin (P<0.05). The acute insulin response (AIR) to 2.5 g of arginine during this infusion of epinephrine was significantly higher (P<0.05) than in controls as were the acute glucagon response (AGR) (P<0.05) and the acute somatostatin response (ASLIR) (P<0.05). Plasma glucose levels increased slightly and transiently during infusion of epinephrine from 99±2 mg/dl to a maximum of 110±3 mg/dl (P<0.05). An IV infusion of 80 ng/kg/min of epinephrine produced plasma epinephrine levels of 2948±281 pg/ml, and increased the baseline pancreatic output of insulin (P<0.05) and glucagon (P<0.05). In contrast, baseline somatostatin output decreased transiently during this high dose infusion of epinephrine. The AIR and ASLIR to arginine were both significantly lower (P<0.05) than those during the infusion of epinephrine at the low dose. The AGR to arginine remained potentiated (P<0.05). Plasma glucose levels increased from 99±3 mg/dl to 119±4 mg/dl (P<0.01). We conclude that the effect of epinephrine on islet hormone secretion is dependent on the plasma level of epinephrine. At stress levels of 900–1000 pg/ml, both insulin and somatostatin secretion are stimulated; only at near pharmacologic, or extreme stress levels, does epinephrine produce net inhibition.     

Hormonal and metabolic changes during hypothermic coronary artery bypass surgery in diabetic and non-diabetic subjects

Hormonal and metabolic responses to hypothermic coronary artery bypass grafting (CABG) were studied in three groups: 8 non-diabetic patients, 8 patients with non-insulin-dependent diabetes mellitus (NIDDM) given a glucose pump priming solution and 8 NIDDM patients given a non-glucose infusion. There were no significant differences in stress hormone responses between NIDDM and non-diabetic patients, with adrenaline concentrations rising 10-fold, noradrenaline 4-fold and cortisol 2 to 3-fold. Glucagon rose significantly during bypass only in the NIDDM patients who did not receive a glucose prime. Comparable marked hyperglycaemia was seen in both glucose primed groups during bypass and exclusion of glucose from the prime in NIDDM patients prevented this major rise. Postoperatively, the rise in insulin in the glucose primed NIDDM patients contrasted with the slower rise in the non-glucose primed NIDDM patients who were also hyperglycaemic by this stage. Perioperative hyperglycaemia in NIDDM patients undergoing CABG can be prevented by using a non-glucose priming solution and by giving insulin infusion, particularly postoperatively.     

Contribution of first trimester fasting plasma insulin levels to the incidence of glucose intolerance in later pregnancy: Tanaka women's clinic study

Aims

To clarify risk factors predictive of glucose intolerance in later pregnancy.

Methods

We prospectively studied 509 pregnant women who visited the obstetrics clinic in Tokyo prior to week 13 of gestation, between September 2008 and January 2010. Biochemical parameters were measured in fasting plasma samples collected at week 8.0 ± 2.0 of gestation. A 50 g glucose challenge test (GCT) was performed between weeks 26 and 29: plasma glucose levels ≥7.8 mmol/l 1 h after ingestion indicated a positive GCT. Logistic regression was performed, adjusting for relevant covariates.

Results

We identified 114 patients with positive GCTs, including 8 with gestational diabetes mellitus (GDM). After correcting for baseline body mass index, only the homeostasis model assessment of insulin resistance value remained a significant predictor of GCT positivity (OR 2.07; 1.21-3.55). We identified threshold values of fasting plasma glucose (FPG) ≥3.66 mmol/l and fasting plasma insulin (FPI) ≥36.69 pmol/l as indicative of a higher risk of positive GCT (OR 2.38; 1.49-3.80).

Conclusions

First trimester FPI levels improve the predictive ability of FPG level on subsequent GCT positivity.     

Diurnal variations in insulin secretion and insulin sensitivity in aged subjects

Summary Glucose tolerance tends to decrease in healthy aged subjects without family history of diabetes. Either reduced insulin secretion or insulin resistance may be responsible. Insulin secretion and insulin sensitivity were studied in 7 aged subjects (68–75 years) and 8 young controls (21–27 years). A 1-mg i.v. glucagon and a 5-U/m² body area i.v. insulin test were run in each subject at 07⁰⁰ and at 19⁰⁰ on two different days to detect diurnal variations. An arginine test was also performed to evaluate pancreatic glucagon behavior. In the evening, young subjects presented a glucose tolerance impairment with significantly decreased plasma insulin levels, and a reduced hypoglycemic effect of exogenous insulin. Resistance to both endogenous and exogenous insulin in the aged was observed in the morning without significant morning/evening variations. Since the response to contra-insular hormones (GH in the insulin test, glucagon in the arginine test) was the same in both age groups, their role in the phenomenon could be ruled out. It is suggested that in the aged a stable reduction in number and/or a change in affinity of insulin receptors may occur. In addition, since again is seen to be associated with the disappearance of diurnal variations in glucose tolerance and insulin secretion and sensitivity, and since a reduction in the receptor level of young healthy subjects in the evening has been reported by some authors, it is suggested that aged subjects may be less able to modulate the binding of insulin to its peripheral receptors in the course of the day.     

Effects of Heparin-induced Non-esterified Free Fatty Acid on Minimal Model-derived Insulin Sensitivity in Individuals with Varying Degrees of Glucose Intolerance

The effects of heparin-induced non-esterified free fatty acid (NEFA) release on insulin sensitivity index were studied in individuals with varying degrees of glucose intolerance and beta cell dysfunction during the frequently sampled intravenous glucose tolerance test (IVGTT). The groups comprised: Group 1 (n = 5): newly diagnosed Type 2 diabetic patients, Group 2 (n = 11): impaired glucose tolerance patients (IGT), and Group 3 (n = 16): healthy normal glucose tolerance subjects. The serum insulin and c-peptide levels were severely blunted in the diabetic patients when compared to both non-diabetic groups. Mean fasting and post-heparin plasma NEFA levels were approximately 1.8 fold greater (p < 0.05) in the diabetic patients when compared to the other two groups. The mean insulin sensitivity index was lowest in the diabetic patients, intermediate in the IGT patients, and highest in the healthy controls. A significant negative relationship was found between the insulin sensitivity index and stimulated NEFA (r = ?0.537, p < 0.008) but not with the fasting NEFA levels in our subjects. In summary, the frequently sampled IVGTT protocol that employs heparin flushes results in marked elevations in NEFA in Type 2 diabetic patients with poor beta cell dysfunction but not in subjects with intermediate or normal glucose tolerance. The higher plasma NEFA levels during heparin injections could worsen the model-derived, insulin sensitivity index and could impair the ability to achieve an acceptable modelling in Type 2 diabetic patients. We therefore suggest heparin should be avoided in such patients when using this protocol.     

内脂素在MIN6胰岛β细胞的表达及葡萄糖和棕榈酸对其表达的影响

大鼠和小鼠胰岛细胞和MIN6细胞均有内脂素表达.胰岛细胞内脂素的表达受葡萄糖(5.5和33.3 mmol/L)和棕榈酸(0.5 mmol/L)的影响(1.0±0.11、1.32±0.18、1.33±0.15、1.72±0.27,与5.5mmol/L葡萄糖组相比,均P<0.05),提示内脂素可能参与胰岛细胞的胰岛素释放的调控.     

Hormonal control of glucose production and pyruvate kinase activity in isolated rat liver cells: influence of hypothyroidism

Hormonal control of glucose production and of -pyruvate kinase activity has been measured in isolated liver cells from fed control and thyroidectomized rats. In hypothyroid rats, sensitivity to isoproterenol as measured by these parameters was increased: the apparent K_0.5 for isoproterenol-induced stimulation of glucose production decreased from 8.0 ± 3 × 10⁻⁶ M in control rats to 2.0 ± 0.2 × 10⁻⁸ M in hypothyroid rats (P < 0.001) and the apparent K_0.5 for inhibition of -pyruvate kinase was 5 ± 2 X 10⁻⁷ M vs. 7 ± 2 × 10⁻⁹ M (P < 0.001) in control and thyroidectomized rats, respectively. Utilisation of specific adrenergic antagonists confirmed increased β-adrenergic responsiveness in hypothyroid rats. This phenomenon was not reversed by 3 days of T₃ treatment (10 μg/100 g body weight). Sensitivity to the -agonist was unchanged by thyroid status. Stimulation of glucose production and inhibition of -pyruvate kinase activity by glucagon and their reversal by insulin were not affected by hypothyroidism. The dose-response curve to vasopressin and its maximal effect measured on stimulation of glucose production were unchanged in thyroidectomized rats. Thus, hypothyroidism produces a specific enhancement of liver β-adrenergic responsiveness without affecting sensitivity to glucagon, insulin and vasopressin.     

Salivary Alpha-Amylase Activity in Relation to Cardiometabolic Status in Japanese Adults without History of Cardiovascular Disease

Aims: Stress is known to be a potential contributor to the development of diabetes and hypertension. However, the biological mechanisms underlying the association between cardiometabolic risk markers and the biological stress response have not yet been determined. Therefore, we examined salivary alpha-amylase and heart rate variability in relation to cardiometabolic status in a sample of healthy Japanese men and women. Methods: Participants (473 men and 1,029 women aged 30-84) underwent a 75 g oral glucose tolerance test after a 10-hr fast. The homeostasis model assessment index for insulin resistance was based on fasting and 2-hr postload glucose and insulin concentrations. Sitting blood pressure was measured twice after rest. A saliva sample was collected in the morning and salivary alpha-amylase was assayed. A 5-min heart rate variability recording was evaluated using time-domain indices of standard deviations of normal-to-normal intervals and root mean square of successive differences. Multivariate linear regression models were used to estimate associations between salivary alpha-amylase and each outcome measure. Results: Salivary alpha-amylase was associated with fasting glucose (β=0.008; 95% CI=0.002, 0.014), 2-hr postload glucose (β=0.023; 95% CI=0.004, 0.041), homeostasis model assessment index for insulin resistance (β=0.032; 95%CI=0.000, 0.064), systolic (β=1.603; 95% CI=0.479, 2.726) and diastolic (β=0.906; 95% CI=0.212, 1.600) blood pressures among women. These associations remained significant after further adjustment for heart rate variability measures. Conclusions: The elevation of salivary alpha-amylase may reflect a dysfunction of the sympathetic nervous system associated with cardiometabolic abnormalities in women.     

肾上腺髓质素前体N端20肽（PAMP）对大鼠血糖及其调节激素的影响

目的 研究肾上腺髓素前体Ｎ端２０肽对大鼠血糖及其调节激素的影响。方法 分别从外周和中枢途径观察ＰＡＭＰ对大鼠血糖及其调节激素的影响,用免疫组化方法对胰腺中的ＰＡＭＰ进行了定位。结果 外周及中枢给予ＰＡＭＰ均可使大鼠血糖显著升高,而前者使血浆胰岛素水平显著下降,胰升糖素水平显著升高;后者使胰岛素水平显著升高,胰升糖素水平变化不大。