Control of insulin secretion during fasting hyperglycemia in adult diabetics and in nondiabetic subjects during infusion of glucose

In obese adult diabetics, the concentration of insulin in venous plasma was unrelated to the degree of hyperglycemia after an overnight fast. However, in these subjects, insulin rose and fell in proportion to the magnitude of change in plasma glucose induced by small intravenous infusions of glucose. The minimal dose of glucose to cause a significant rise in insulin above the fasting level was similar in normal subjects, obese nondiabetic subjects, and in obese, hyperglycemic adult diabetics. This dose lay between infusion of 60 and 100 mg of glucose per min for 30 min. These results suggested that the secretion of insulin was under regulation by changes in blood glucose but was not stimulated in proportion to the stable raised blood glucose concentration of the hyperglycemic diabetic. Artificial hyperglycemia was induced in fasting normal subjects by constant intravenous infusion of glucose at rates of 100-250 mg of glucose per min for periods up to 8 hr. Plasma glucose rose during the 1st hr of infusion and then remained constantly elevated for up to 8 hr. The concentration of plasma insulin paralleled that of plasma glucose. During the period of constant hyperglycemia and elevated insulin, superimposition of a brief additional glucose load resulted in a prompt rise in glucose and insulin, both returning to the previous elevated levels.Thus in normals as well as obese diabetics, stable hyperglycemia does not produce a pancreatic response sufficient to return the blood glucose to an arbitrary normal fasting concentration, yet the beta cells remain readily responsive to a change in plasma glucose. These data suggest that the beta cells do not operate as a control system with an absolute reference point when presented with systemic hyperglycemia. The behavior of the beta cells during hyperglycemia in the fasting obese adult diabetic suggests that the regulation of the basal insulin secretion may not be determined by factors directly related to the prevailing concentration of glucose. It is postulated that the beta cells adapt to hyperglycemia perhaps through the operation of controls directed toward a normal delivery of free fatty acids or some other cellular metabolic substrate during fasting.     

Lipoprotein concentrations in untreated adult onset diabetes mellitus and the relationship of the fasting plasma triglyceride concentration to insulin secretion.

Plasma lipoprotein concentrations in 64 untreated adult onset diabetics were compared to the lipoprotein levels found in non diabetics. No significant difference was found. The relationship of the fasting plasma triglyceride concentration to the plasma immunoreaction insulin response to 50 g glucose orally was investigated. Using correlation analysis a significant and insulin response in the non diabetics but not in the diabetics.     

Twice-daily humulin ultralente insulin decreases morning fasting hyperglycemia.

OBJECTIVE--To test whether a two-injection regimen of HUL/R would improve FBG and metabolic control in pediatric IDDM patients with a dawn rise in FBG compared with our standard twice-daily therapy, HL/R. RESEARCH DESIGN AND METHODS--Seventy-seven patients with fasting hyperglycemia (prebreakfast mean FBG greater than or equal to 8.3 mM (150 mg/dl) during the preceding 2 wk) were evaluated with twice-weekly midsleep (0230-0330) FBG for 2 wk. Forty-seven patients (61%) had a mean dawn rise between midsleep and prebreakfast of greater than or equal to 2.8 mM (50 mg/dl). Patients continued on HL/R for an additional 4 wk, after which 31 patients were then randomized into a double-blind 12-wk trial of either HUL/R (n = 14) or HL/R (n = 17) administered before breakfast and the evening meal. Midsleep FBG was obtained twice weekly with weekly insulin adjustment as needed to optimize glycemic control. FBG was monitored and verified with memory glucometers (Glucometer M). HbA1c levels were measured at the time of physician visits at 0, 6, and 12 wk. RESULTS--Prebreakfast FBG was lower in the HUL/R-treated patients (10.6 +/- 0.6 vs. 12.6 +/- 0.6 mM [191 +/- 6.4 vs. 227 +/- 11.2 mg/dl], P less than 0.02). The dawn rise was diminished in the HUL/R patients (0.5 +/- 0.5 vs. 2.6 +/- 0.7 mM [9 +/- 8.3 vs. 46 +/- 11.7 mg/dl], P less than 0.02). FBG at lunch, dinner, bedtime, and midsleep were similar in both groups, and HbA1c did not differ between groups or change significantly in either group during the 12-wk trial. Insulin dose, percentage R, day-night dosage split, and episodes of hypoglycemia (FBG less than 3.3 mM [60 mg/dl]) were similar in both groups. CONCLUSIONS--A 12-wk trial of twice-daily HUL/R improved fasting glycemia in pediatric patients with a dawn rise but did not improve metabolic control as measured by HbA1c.     

Glucagon-induced insulin secretion in normal diabetic subjects.

Eight normal subjects and ten diabetic patients were studied to compare the response of plasma insulin to glucagon with that to glucose and tolbutamide. Oral glucose tolerance test, glucagon test and tolbutamide-glucagon test were performed at intervals of several days. In glucose tolerance test, insulin response was reduced in the patients with severe diabetes. Plasma insulin increased and reached the peak 3 min after glucagon injection (glucagon I) in the normal controls, while plasma insulin response was reduced in diabetic patients, especially in the severe diabetics. In the normal controls plasma insulin rose and reached the peak 6 min after the tolbutamide injection and thereafter fell to the initial level. Glucagon injection following tolbutamide (glucagon II) caused the rise in insulin in the control subjects. In diabetics insulin response to either tolbutamide or glucagon I was reduced. Tolbutamide or glucagon II caused a significant difference in plasma insulin response in all the diabetic groups compared with the normal subjects, while glucose or glucagon I showed a significant increment of plasma insulin between the normal subjects and the severe diabetics. These results suggest that injection of tolbutamide as well as glucagon II provides a definite discrimination of insulin response in diabetics from the normal controls. The usefulness of the tolbutamide-glucagon test in the diagnosis of diabetes mellitus was discussed. -- glucose tolerance test; glucagon test; tolbutamide-glucagon test; plasma insulin.     

Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats.

Insulin resistance is characteristic of the diabetic state. To define the role of hyperglycemia in generation of the insulin resistance, we examined the effect of phlorizin treatment on tissue sensitivity to insulin in partially pancreatectomized rats. Five groups were studied: group I, sham-operated controls; group II, partially pancreatectomized diabetic rats with moderate glucose intolerance; group III, diabetic rats treated with phlorizin to normalize glucose tolerance; group IV, phlorizin-treated controls; and group V, phlorizin-treated diabetic rats restudied after discontinuation of phlorizin. Insulin sensitivity was assessed with the euglyemic hyperinsulinemic clamp technique in awake, unstressed rats. Insulin-mediated glucose metabolism was reduced by approximately 30% (P less than 0.001) in diabetic rats. Phlorizin treatment of diabetic rats completely normalized insulin sensitivity but had no effect on insulin action in controls. Discontinuation of phlorizin in phlorizin-treated diabetic rats resulted in the reemergence of insulin resistance. These data demonstrate that a reduction of beta-cell mass leads to the development of insulin resistance, and correction of hyperglycemia with phlorizin, without change in insulin levels, normalizes insulin sensitivity. These results provide the first in vivo evidence that hyperglycemia per se can lead to the development of insulin resistance.     

Early-morning hyperglycemia in diabetic individuals treated with continuous subcutaneous insulin infusion

Significantly early-morning hyperglycemia was observed in insulin-dependent diabetic individuals who were otherwise well controlled while receiving a continuous subcutaneous insulin infusion (CSII) at standard doses. We measured the levels of the five key counterregulatory hormones (CRH) throughout the night for a total of 10 patient-nights in four such patients. No abnormalities in the patterns of glucagon, cortisol, growth hormone, epinephrine, or norepinephrine secretion were observed. Stepping up the daytime basal infusion rate in six affected patients before bedtime by 37.0 +/- 7.5% and maintaining the increased infusion until breakfast significantly blunted this early-morning hyperglycemia without causing significant early nighttime hypoglycemia. Plasma glucose concentrations before breakfast averaged 106.8 +/- 13.0 mg/dl after increase of the overnight basal infusion rate as compared with 269.8 +/- 39.1 mg/dl while receiving a single basal rate over 24 h (P less than 0.02). Thus, the "dawn phenomenon" may occur in patients receiving CSII by an unmodified algorithm and may be obviated by a carefully determined step-up in nocturnal basal infusion rate. The mechanism responsible for this phenomenon of increased early-morning insulin need remains to be elucidate.     

Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects

The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.     

Equilibrium binding studies of insulin antibodies in diabetic subjects.

Equilibrium binding of insulin to human insulin antibodies from diabetic subjects has been studied by two methods. Results obtained by using a nondissociating gel filtration assay differed from those obtained by a conventional competitive binding method. Both methods yield data consistent with two classes of insulin binding site, having association constants of approximately 10(9) and 10(7) liter/mol. The principal differences are the higher association constant and lower number of binding sites for the high-affinity binding component, observed with the gel filtration method. In the conventional competitive binding assay, damaged radioligand, dissociation of the binding complex, or limitations of ligand availability may be responsible for the erroneous results. Data from nine diabetic patients indicate that insulin resistance and stability of diabetes cannot be explained by the binding properties of insulin antibodies alone.     

Peripheral resistance to the cellular action of insulin in obese diabetic subjects in vivo

1. The concentrations of adenosine 3': 5'-cyclic monophosphate (cyclic AMP) in human adipose tissue were studied after intravenous insulin administration (0.3 unit/kg body weight) in obese diabetic and obese non-diabetic subjects. 2. The declines in plasma glucose, glycerol and free fatty acids in the two groups after insulin were similar if allowances were made for the fasting hyperglycaemia in the diabetic subjects. 3. Insulin in vivo lowered the concentrations of cyclic AMP in adipose tissue from non-diabetic subjects. 4. Insulin administration in vivo did not alter the tissue concentrations of cyclic AMP in adipose tissue of obese diabetic subjects. This lack of effect of insulin provides evidence for tissue resistance in vivo to the action of insulin in diabetes mellitus.     

Effect of pinitol treatment on insulin action in subjects with insulin resistance

OBJECTIVE: Endogenous low-molecular-weight glycans containing pinitol (3-O-methyl-D-chiro-inositol) and D-chiro-inositol are thought to mediate certain actions of insulin. We tested the hypothesis that oral administration of soybean-derived pinitol would improve insulin sensitivity in obese subjects (BMI = 36.6 kg/m2) with diet-treated type 2 diabetes or glucose intolerance (HbA1c = 6.8%). RESEARCH DESIGN AND METHODS: There were 22 subjects randomized to receive either pinitol 20 mg x kg(-1) x day(-1) (n = 12) or placebo (n = 10) in a 28-day double-blinded trial. RESULTS: No toxicity due to the pinitol was observed during the study The sensitivity of glucose and lipid metabolism to insulin were assessed by measurement of whole-body glucose, palmitate, and glycerol kinetics during basal conditions and a hyperinsulinemic-euglycemic clamp. Metabolic measurements were made at baseline and again at the end of the study Final plasma levels of pinitol were 48-fold (1.06 +/- 0.15 vs. 0.02 +/- 0.01 micromol/l, P < 0.0001) and D-chiro-inositol levels 14-fold (0.56 +/- 0.08 vs. 0.04 +/- 0.02 micromol/l, P < 0.0001) greater in the pinitol group compared with placebo. CONCLUSIONS: Four weeks of pinitol treatment did not alter baseline glucose production, insulin-mediated glucose disposal, or rates of appearance of free fatty acids and glycerol in plasma. We conclude that plasma levels of both pinitol and D-chiro-inositol are very responsive to pinitol ingestion, but insulin sensitivity does not increase after pinitol treatment in individuals with obesity and mild type 2 diabetes.     

Metabolic response to fasting exercise in adolescent insulin-dependent diabetic subjects treated with continuous subcutaneous insulin infusion and intensive conventional therapy

The metabolic effects of moderate exercise in the fasting state were examined in 12 insulin-dependent diabetic adolescents treated with continuous subcutaneous insulin infusion (CSII) or intensive conventional therapy (ICT). Six patients received their usual afternoon dose the evening before the study and six received their usual infusion rate during exercise. Insulin was injected subcutaneously in the abdominal wall. Exercise was performed on a bicycle ergometer for 45 min at 50% maximum oxygen consumption. Resting plasma glucose values during both CSII (114 +/- 18 mg/dl, P less than 0.02) and ICT (136 +/- 30 mg/dl, P less than 0.01) were higher than normal (77 +/- 11 mg/dl). Diabetic patients receiving CSII showed a sharp decrease in glycemia after 45 min of exercise (77 +/- 18 mg/dl, P less than 0.02). In contrast, in patients receiving ICT and in control subjects plasma glucose did not change during exercise or recovery. Insulin levels decreased significantly during exercise in the control subjects while there was no change in plasma free insulin levels during exercise in the diabetic subjects. Profiles of intermediary metabolites in response to exercise were similar in all groups with no significant differences in resting values between diabetic subjects and controls. Continuous subcutaneous insulin infusion provides near-normoglycemia in the insulin-dependent diabetic adolescent. However, with the basal insulin infusion rate necessary to achieve near-normal fasting blood glucose levels, moderate exercise in the postabsorptive state may result in hypoglycemia with CSII.     

Plasma adiponectin plays an important role in improving insulin resistance with glimepiride in elderly type 2 diabetic subjects

OBJECTIVE: We investigated the effect of glimepiride, a third-generation sulfonylurea hypoglycemic agent, on insulin resistance in elderly patients with type 2 diabetes, in connection with plasma adiponectin and 8-epi-prostagrandin F2alpha (8-epi-PGF2alpha), an oxidative stress marker. RESEARCH DESIGN AND METHODS: A total of 17 elderly patients with type 2 diabetes received 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of beta-cell function, HbA(1c), C-peptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2alpha, tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinemic-euglycemic clamp. RESULTS: After 8 weeks of glimepiride treatment, significant reductions were observed in HbA(1c) (from 8.4 +/- 1.9 to 6.9 +/- 1.0%), HOMA-IR (from 2.54 +/- 2.25 to 1.69 +/- 0.95%), and plasma TNF-alpha concentrations (from 4.0 +/- 2.0 to 2.6 +/- 2.5 pg/ml). MCR-g was significantly increased from 3.92 +/- 1.09 to 5.73 +/- 1.47 mg. kg(-1). min(-1). Plasma adiponectin increased from 6.61 +/- 3.06 to 10.2 +/- 7.14 micro g/ml. In control subjects, who maintained conventional treatment, no significant changes were observed in any of these markers. CONCLUSIONS: Glimepiride remarkably improved insulin resistance, suggested by a significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA(1c) without changing extrapancreatic beta-cell function and urine CPR. Increased plasma adiponectin and decreased plasma TNF-alpha may underlie the improvement of insulin resistance with glimepiride.     

藏族老年潜在高血糖者胰岛素抵抗与动脉粥样硬化的关系

目的:代谢综合征会导致动脉粥样硬化形成,但其程度具有种族差异性。观察不同胰岛素抵抗指数藏族老年患者动脉粥样硬化相关指标差异,分析藏族老年人胰岛素抵抗与动脉粥样硬化的关系。方法:①实验于2006-01/08由解放军西藏军区总医院和解放军总医院共同完成。共纳入760例藏族潜在高血糖患者,男464例,女296例;年龄(66±10)岁。有糖尿病家族史;曾经发现空腹或餐后血糖异常;明确诊断为糖耐量低减或2型糖尿病;均对检测指标知情同意。②对所有参试者进行体检、询问病史及口服75g葡萄糖耐量试验,采静脉血检测血脂及胰岛素水平,B型超声检查双侧颈总动脉内中膜厚度,稳态模型计算胰岛素抵抗指数,根据该指数0.21￣0.77,0.78￣1.06,1.07￣1.30,1.31￣1.84,1.85￣10.57分5组进行观察。③计量和计数资料差异比较分别采用方差分析和χ2检验。结果:患者760例均进入结果分析。①不同胰岛素抵抗指数患者平均内中膜厚度与内膜光滑程度比较,差异明显(F=7.39,18.48,P<0.01),胰岛素抵抗指数大的患者动脉硬化程度也较高。②多元回归分析结果显示,增龄、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、胰岛素抵抗指数自然对数与内中膜厚度独立相关(Beta值=0.237,0.182,0.263,0.216,0.284,P<0.05￣0.01),其中胰岛素抵抗指数自然对数的Beta值最大,表明胰岛素抵抗在动脉粥样硬化形成过程中起最重要的作用。③随着胰岛素抵抗指数增加,糖耐量异常、糖尿病、高血压、冠心病患病率显著升高(P<0.01)。不同胰岛素抵抗指数参试者的血糖、血脂、胰岛素水平差异明显(P<0.01)。结论:在藏族老年人群中,胰岛素抵抗参与动脉粥样硬化的形成,胰岛素抵抗指数大的患者动脉硬化程度也较高。     

Trimetazidine diminishes fasting glucose in rats with fasting hyperglycemia: a preliminary study

Trimetazidine is a drug with cardioprotective properties used in coronary artery disease. Its effect has been attributed to the inhibition of the long chain fatty acids intramitochondrial transport via carnitine-palmitoyl-transferase-1. Clinical evidence supports the possibility that trimetazidine is able to improve the fasting glycemia in diabetic patients. For this reason, the objective of the present study was to determine the effect of trimetazidine on serum glucose of Sprague-Dawley rats with fasting hyperglycemia. All animals received water and food "ad libitum." Blood glucose was measured weekly to confirm fasting hyperglycemia in rats. The rats were treated for 1 month with trimetazidine (1 mg/kg), and blood samples were collected (in the fasting period) on the last day of treatment (the 30th day); and then on the 15th day posttreatment, measurements of plasma glucose were taken. Fasting plasma levels after 30 days of trimetazidine administration decreased significantly from 141.2 +/- 3.3 mg/dL (pre-drug) to 120.9 +/- 5.8 mg/dL (P<0.01). 15 days after the end of treatment, fasting plasma glucose levels (137.0 +/- 7.0 mg/dL) were close to the pretreatment levels but significantly different (P<0.05) from levels on day 30 of treatment. These data suggest that trimetazidine improved blood glucose utilization in rats with fasting hyperglycemia.     

Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects.

To determine if both phases of glucagon secretion are excessive in diabetes, arginine was admimistered intravenously as pulses and as infusions to normal subjects, insulin-dependent diabetics, and noninsulin-requiring diabetics. The acute phase of glucagon secretion, in response to arginine pulses at four different doses (submaximal to maximal alpha-cell stimulating), was indistinguishable in terms of timing, peak levels attained, and total increments comparing controls and diabetics. During the first half of the arginine infusion (500 mg/kg over 30 min) the glucagon rise in controls and diabetics was similar (P greater than 0.1), whereas during the last half of the infusion excessive glucagon levels were seen in the diabetics. No difference in the glucagon responses to arginine administered as either a pulse or an infusion was observed between the two types of diabetics. The acute phase responses of insulin to intravenous, maximal stimulating doses of glucose (20 g) and arginine (2.5 g) were measured in five insulin-independent diabetics. Although the acute insulin response to arginine was normal, there was marked attentuation of the early beta-cell response upon stimulation by glucose. From these results we conclude that although in diabetes excessive glucagon levels are observed with chronic arginine stimulation, the acute phase of glucagon secretion in response to arginine is normal. In addition, the beta-cell in noninsulin-requiring diabetics, although acutely hyporesponsive to glucose, remains normally responsive to another stimulus, arginine.