Abnormalities in insulin secretion in type 2 diabetes mellitus

Type 2 diabetes mellitus is a multifactorial disease, due to decreased glucose peripheral uptake, and increased hepatic glucose production, due to reduced both insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including absence of pulsatility, loss of early phase of insulin secretion after glucose, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. beta-cell dysfunction is genetically determined and appears early in the course of the disease. The interplay between insulin secretory defect and insulin resistance is now better understood. In subjects with normal beta-cell function, increase in insulin is compensated by an increase in insulin secretion and plasma glucose levels remain normal. In subjects genetically predisposed to type 2 diabetes, failure of beta-cell to compensate leads to a progressive elevation in plasma glucose levels, then to overt diabetes. When permanent hyperglycaemia is present, progressive severe insulin secretory failure with time ensues, due to glucotoxicity and lipotoxicity, and oxidative stress. A marked reduction in beta-cell mass at post-mortem examination of pancreas of patients with type 2 diabetes has been reported, with an increase in beta-cell apoptosis non-compensated by neogenesis.     

The rise and fall of insulin secretion in type 1 diabetes mellitus

An understanding of the natural history of beta cell responses is an essential prerequisite for interventional studies designed to prevent or treat type 1 diabetes. Here we review published data on changes in insulin responses in humans with type 1 diabetes. We also describe a new analysis of C-peptide responses in subjects who are at risk of type 1 diabetes and enrolled in the Diabetes Prevention Trial-1 (DPT-1). C-peptide responses to a mixed meal increase during childhood and through adolescence, but show no significant change during adult life; responses are lower in adults who progress to diabetes than in those who do not. The age-related increase in C-peptide responses may account for the higher levels of C-peptide observed in adults with newly diagnosed type 1 diabetes compared withhose in children and adolescents. Based on these findings, we propose a revised model of the natural history of the disease, in which an age-related increase in functional beta cell responses before the onset of autoimmune beta cell damage is an important determinant of the clinical features of the disease. Electronic Supplementary Material Supplementary material is available for this article at     

Indomethacin decreases insulin secretion in patients with type 2 diabetes mellitus

In healthy subjects, basal endogenous glucose production (EGP) is partly regulated by paracrine intrahepatic factors. Administration of indomethacin, an inhibitor of prostaglandin synthesis, resulted in a transient stimulation of EGP without changes in glucoregulatory hormone concentrations. It is unknown whether similar paracrine factors influence basal EGP in type 2 diabetes mellitus. The effects of 150 mg indomethacin, a nonendocrine stimulator of glucose production in healthy adults, and placebo on EGP were measured in a randomized placebo-controlled study in patients with type 2 diabetes mellitus (3 men and 3 women; mean age, 58.5 years; mean body mass index, 28.6 kg x m(-2)). EGP was measured before and for 6 hours after administration of placebo/indomethacin, by a primed, continuous infusion of [6,6-2H2]glucose. After indomethacin, plasma glucose and EGP increased in all subjects by 14% (P < .05) and 48% (P < .05), respectively. In the control experiment, plasma glucose and EGP declined gradually in all subjects by 22% (P < .001) and 17% (P = .004), respectively. The stimulation of glucose production coincided with the inhibition of insulin secretion by 52% within 1 hour after administration of indomethacin (P < .001). In the control experiment, insulin secretion decreased gradually by 18% after 6 hours (P < .001). Thus, indomethacin inhibits insulin secretion and stimulates EGP in type 2 diabetes.     

Aminophylline stimulates insulin secretion in patients with type 2 diabetes mellitus

In healthy subjects, paracrine factors partly regulate insulin secretion and basal endogenous glucose production. Administration of pentoxifylline, an adenosine receptor antagonist, inhibits transiently endogenous glucose production in healthy humans without any changes in glucoregulatory hormone concentrations. To evaluate the modulatory role of adenosine on endogenous glucose production and basal insulin secretion in type 2 diabetes, aminophylline, a potent adenosine receptor antagonist, was administered intravenously to 5 patients with type 2 diabetes mellitus in a saline-controlled study. Endogenous glucose production was measured before and during 6 hours after administration of aminophylline/saline by primed, continuous infusion of [6,6-(2)H(2)]glucose. During both experiments, the decrease in plasma glucose concentration was similar (16% v 18% from basal, not significant [NS]). After aminophylline administration, basal endogenous glucose production was transiently inhibited within 15 minutes to 70% from basal, whereas it did not change significantly in the control experiment (P =.02). The inhibition of glucose production coincided with stimulation of insulin secretion to 144% from basal 90 minutes after the administration of aminophylline (P =.008). In the control experiment insulin secretion decreased gradually by 29% during 6 hours. We conclude that aminophylline inhibits endogenous glucose production in type 2 diabetes by stimulation of insulin secretion. Paracrine factors, such as adenosine, may be involved in the regulation of basal insulin secretion in type 2 diabetes mellitus.     

Importance of early phase insulin secretion to intravenous glucose tolerance in subjects with type 2 diabetes mellitus.

Insulin secretion is impaired in type 2 diabetes with the early response being essentially absent. The loss of this early insulin secretion is hypothesized to be important in the deterioration of glucose tolerance. To determine whether enhancement of the early-phase insulin response can enhance glucose tolerance, we administered 1) 120 mg nateglinide, an insulinotropic agent that enhances early insulin secretion; 2) 10 mg glyburide, which enhances the later phases of insulin secretion; or 3) placebo in random order to 21 subjects with type 2 diabetes (14 males and 7 females; aged 59.2 +/- 2.1 yr, x +/- SEM; body mass index 29.7 +/- 1.0 kg/m(2); fasting plasma glucose 8.1 +/- 0.1 mM). beta-Cell function was quantified as the incremental area under the curve for different time periods for the 5 h following iv glucose administration and glucose tolerance as the glucose disappearance constant (Kg) from 10 to 60 min. Insulin release commenced immediately after nateglinide administration, even before glucose injection, but this was not observed with glyburide. Both nateglinide and glyburide enhanced glucose-induced insulin release, compared with placebo (area under the curve -15-300 min: nateglinide 23,595 +/- 11,212 pM/min, glyburide 54,556 +/- 15,253 pM/min, placebo 10,242 +/- 2,414 pM/min). The profiles of insulin release demonstrated significant enhancement of release between -15 and 30 min for nateglinide, compared with glyburide and between 60 and 300 min for glyburide over nateglinide. Kg increased by 15% with nateglinide (0.87 +/- 0.04%/min), but it did not increase significantly with glyburide (0.79 +/- 0.04%/min), compared with placebo (0.76 +/- 0.04%/min). The enhancement of insulin release by glyburide resulted in a lower minimal glucose concentration with glyburide (3.8 +/- 0.2 mM), compared with nateglinide (5.0 +/- 0.2 mM) and placebo (5.9 +/- 0.2 mM). Thus, enhancement of the early phase of insulin secretion improves iv glucose tolerance, whereas delaying it by 30 min results in a slower rate of glucose disappearance for the first 2 h after iv glucose administration. Further, the differences in the kinetics of nateglinide and glyburide action results in continued insulin release with glyburide despite the fact that glucose levels have returned to basal, thus resulting in a further reduction in glucose levels and a lower nadir.     

Prostaglandins, insulin secretion and diabetes mellitus

The islets of Langerhans have the enzymatic equipment permitting the synthesis of the metabolites of arachidonic acid: cyclo-oxygenase and lipo-oxygenase. Numerous studies have shown that cyclo-oxygenase derivatives, mainly PGE2, reduce the insulin response to glucose whereas lipo-oxygenase derivatives, mainly 15-HPETE, stimulate insulin secretion. So, for instance, drugs that increase prostaglandins synthesis as colchicine or furosemide inhibit insulin secretion while non steroid anti-inflammator drugs, mainly salicylates, which inhibit cyclo-oxygenase, enhance the insulin response to various stimuli. In type-2 (non insulin-dependent) diabetes, an increased sensitivity to endogenous prostaglandins has been proposed as a possible cause for the insulin secretion defect which characterizes this disease. Play in favor of this hypothesis the fact that the administration of PGE inhibits the insulin response to arginine in type-2 diabetics but not in normal subject and the fact that the administration of salicylates could improve the insulin response to glucose in some of these patients.     

HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion

Aims/hypothesis

We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona.

Methods

Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA, and with type 2 diabetes mellitus and prediabetic traits.

Results

The A allele at rs9268852, which tags HLA-DRB1*02(1602), was associated both with higher HLA-DRB1 mRNA expression (n?=?133, p?=?4.27?×?10^?14) and decreased risk of type 2 diabetes (n?=?3,265, OR 0.723, p?=?0.002). Among persons with normal glucose tolerance (n?=?266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p?=?0.005), higher mean 30?min insulin concentration during an oral glucose tolerance test (p?=?0.017) and higher body fat percentage (p?=?0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity.

Conclusions/interpretation

HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.     

Suppression of insulin secretion by falling plasma glucose levels is impaired in type 2 diabetes

The ability of Type 2 diabetic patients to suppress islet B-cell secretion in response to falling plasma glucose levels has been studied with two different protocols. (1) Five diet-treated diabetic patients and 6 normal subjects were studied after the termination of a hyperglycaemic clamp at 15 mmol l-1 for 150 min, with the plasma glucose levels then being allowed to fall and the glucose clamp re-established at 10 mmol l-1. The plasma insulin levels fell in normal subjects from 178 +/- 141 (+/- SD) mU l-1 at the end of the 15 mmol l-1 clamp to 147 +/- 97 mU l-1 (p less than 0.02) 20 min later, whereas in diabetic patients there was no significant change from 61 +/- 41 to 56 +/- 35 mU l-1, respectively (NS). (2) The second study was performed to assess the turn-off of islet B-cell secretion with diabetic patients and normal subjects starting at comparable plasma insulin levels. Twelve diet-treated diabetic patients and 11 normal subjects were given a continuous low-dose glucose infusion for 60 min at a rate of 5 mg kg-1 ideal body weight min-1, after which the infusion was turned off and the plasma glucose level allowed to fall.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early disturbances in insulin secretion in the development of type 2 diabetes mellitus

In-vitro studies of mouse oocytes have provided evidence that two closely related sterols, subsequently named meiosis-activating sterols (MAS), can overcome the inhibitory effect of hypoxanthine on resumption of meiosis. These sterols are synthesized by cytochrome P450 (CYP) lanosterol 14alpha-demethylase (LDM), a key enzyme in cholesterol biosynthesis. Our studies in the rat with specific inhibitors and molecular approaches did not support the hypothesis that MAS is an obligatory step in the stimulation of the resumption of meiosis. (i) Specific inhibitors of MAS synthesizing enzymes did not prevent spontaneous or LH-stimulated meiosis at doses that have previously been shown to effectively suppress LDM activity. At higher doses, they caused degeneration of oocytes. (ii) The timing of LDM expression in the ovary was incompatible with a role for MAS in meiosis. (iii) The preferential localization of LDM protein in the oocytes suggests MAS production in oocytes, rather than its transport from the somatic compartment as expected by the suggested role of MAS in the regulation of meiosis as a putative cumulus-oocyte signal molecule. (iv) AY-9944, which supposedly increases MAS levels by inhibiting its metabolism, induced the maturation of follicle-enclosed oocytes that was much delayed as compared with gonadotropic stimulation. Thus, the resumption of meiosis induced by added MAS [Biol. Reprod. 61 (1999) 1362, Biol. Reprod. 64 (2001) 418] or presumed endogenous MAS accumulation by AY-9944, resulted in oocyte maturation with remarkably slower kinetics than observed with LH stimulation. This delay in meiosis after MAS stimulation, the studies with LDM inhibitors and its spatial and temporal expression, cast serious doubts whether MAS is indeed mediating the meiosis inducing action of the gonadotropins, as suggested.     

Glucagon-stimulated insulin secretion in patients with type 2 diabetes mellitus: support for the concept of glucose toxicity.

Parameters of blood glucose control and insulin secretion were evaluated in 114 patients with type 2 diabetes mellitus, who were no longer controlled satisfactorily by maximal doses of oral hypoglycaemic agents, and compared with those obtained in 11 healthy control subjects, 32 patients with recently-diagnosed type 2 diabetes, and 16 tablet-treated and 36 insulin-treated patients. Newly-diagnosed patients were slightly younger (60 +/- 13 yr) and had a slightly higher body mass index (29.4 +/- 6.5 kg/m2). Known duration of diabetes was 9 yr (range 1-37) in secondary failure, and 11 yr (range 1-31) in insulin-treated patients. Fasting blood glucose was the highest (13.8 +/- 2.8 mmol/l) in secondary failure and newly-diagnosed patients (12.6 +/- 3.8 mmol/l) compared to tablet-treated (8.7 +/- 3.3 mmol/l) and insulin-treated patients (9.6 +/- 3.2 mmol/l, p less than 0.05). HbA1c levels were comparably elevated. In insulin-treated patients, fasting plasma C-peptide levels were lower relative to the mutually comparable levels in the other 3 diabetic groups. Fasting plasma insulin levels did not differ between the 4 diabetic groups. C-peptide release after glucagon (C-peptide AUC) was comparable in all 4 diabetic groups, although in tablet-treated patients the ratio C-peptide AUC/fasting blood glucose was higher (p less than 0.05). We conclude that the clinical usefulness of determining residual insulin secretion in type 2 diabetic patients is limited, and that the similar reduction of insulin secretion in severely hyperglycaemic newly-diagnosed and secondary failure type 2 diabetic patients supports the concept of "glucose toxicity".     

Relationship between glucose utilization by tissues and residual insulin secretion and their role in the genesis of hyperglycemia in type I diabetes mellitus]

Altogether 67 patients aged 16 to 50 suffering from insulin dependent diabetes mellitus (IDDM) of various duration were investigated to study the effect of peripheral sensitivity to insulin on genesis to hyperglycemia in type I diabetes mellitus. Residual beta-cell insulin secretory function was assessed by the level of C-peptide in a standard food test, and the rate of glucose utilization by tissues was studied by the clamp-method under the conditions of normoglycemia. The results obtained indicate the role of a decrease in peripheral sensitivity to insulin in genesis of hyperglycemia in diabetes mellitus, type I, and the presence of reciprocal interactions between glucose utilization and insulin secretion in IDDM patients and in controls.     

2型糖尿病第1时相胰岛素分泌受损治疗策略

2型糖尿病(T2DM)两大发病机制是胰岛素抵抗和胰岛细胞分泌受损。研究表明，有T2DM相似遗传背景的人群中，如同卵双生子或T2DM的一级亲属，第1时相胰岛素分泌减低。B细胞第1时相胰岛素分泌受损与糖尿病个体从糖耐量正常(NGT)向糖耐量受损(IGT)，并向糖尿病的转归有关，并且可预测糖尿病进程，是糖尿病发病的独立危险因素。     

血脂异常对2型糖尿病患者胰岛素分泌功能的影响

目的 探讨血脂异常对T2DM患者胰岛素分泌功能的影响.方法 初诊的T2DM患者100例,未经调脂和降糖治疗,根据血脂水平分为血脂正常组(A组)、单纯TG升高组(B组)和混合血脂升高组(C组),以30名健康者作对照(NC组),采用HOMA-β评价β细胞分泌功能.结果 与NC组比较,A、B、C三组的HOMA-β均明显降低(P＜0.01);与A组比较,B、C组的HOMA-β降低(P＜0.01);B、C组之间比较差异无统计学意义(P＞0.05).HOMA-β相关因素回归分析显示TG为独立影响因素.结论 TG升高可降低T2DM患者的胰岛素分泌功能,TC没有独立于TG以外的降低胰岛素分泌功能的作用.     

The first and second phase of insulin secretion in naive Chinese type 2 diabetes mellitus

Impaired insulin secretion (ISEC) has been recognized as one of the most important pathophysiologies of type 2 diabetes mellitus. There are 2 phases of ISEC: the first phase (first ISEC) and second phase (second ISEC). This study aimed to evaluate the 2 phases of ISEC in newly diagnosed type 2 diabetes mellitus patients. Fifty-two drug-naive type 2 diabetes mellitus patients were given 2 tests: a modified low-dose graded glucose infusion (M-LDGGI) and frequent sample intravenous glucose tolerance test. The M-LDGGI is a simplified version of the Polonsky method. Two stages of intravenous infusion of glucose with different rates were given, starting from 2 mg/(kg min) and then followed by 6 mg/(kg min). Each stage was maintained for 80 minutes. The results were interpreted as the slope of the changes of plasma insulin against the glucose levels. The slope of these curves was regarded as the second ISEC and used as the criterion for grouping-the responders and nonresponders. The responders are older and had higher body mass index and log (homeostasis model assessment of β-cell function) (log HOMA-β) but lower fasting plasma glucose and hemoglobin A_1c (HbA_1c) than the nonresponders. Significant correlations were only noted between the second ISEC and first ISEC (r = 0.278, P = .046) and between the second ISEC and log HOMA-β (r = 0.533, P = .000). Correlation between different parameters and HbA_1c was also evaluated. Only second ISEC and log HOMA-β were correlated significantly with HbA_1c (r = −0.388, P = .015 and r = −0.357, P = .026, respectively). In type 2 diabetes mellitus, subjects with higher second ISEC are older and have higher body mass index. At the same time, second ISEC is the most important factor for determining glucose levels in naive Chinese type 2 diabetes mellitus patients. The first and second ISECs were only modestly correlated, which indicated that the deterioration of these 2 phases was not synchronized. Finally, we also recommend using the M-LDGGI for quantifying second ISEC. This practical method could be done in many centers without difficulty.