The contribution of hyperglycaemia and hypoinsulinaemia to the insulin resistance of streptozotocin-diabetic rats

Summary The relative contribution of hyperglycaemia and hypoinsulinaemia was evaluated in rats made diabetic by streptozotocin administration. Four groups of rats were studied: untreated normal rats; streptozotocin-diabetic; streptozotocin-diabetic treated with phlorizin (0.4 mg/kg body weight per day); streptozotocin-diabetic mildly treated with insulin (0.7 IU/day). In all groups, insulin action (responsiveness) was assessed with the euglycaemic (5.3 mmol/l) hyperinsulinaemic (524 mU/l) clamp technique combined with ³H-2-deoxy-D-glucose method, enabling determination of the glucose utilization index in various tissues. Responsiveness of the overall glucose utilization process to insulin was reduced by 28% in streptozotocin-diabetic rats (12.0±1.2 vs 16.5±0.6 mg·kg^–1·min^–1, p<0.001). This was associated with a significant reduction (p<0.05) in the glucose utilization index in all muscles studied (average=17.0 vs 32.1 ng·mg of tissue^–1·min^–1), in the heart (19.6 vs 39.5 ng·mg^–1·min^–1), brown adipose tissue (98.9 vs 178.0 ng·mg^–1·min^–1), skin (6.4 vs 13.1 ng·mg^–1·min^–1). Phlorizin treatment normalized plasma glucose levels without affecting those of insulin, and restored overall glucose utilization to normal (16.6±1.0mg·kg^–1·min^–1). This normalization was accompanied by a normalization of the glucose utilization index in all muscle types studied (29.2 ng·mg^–1·min^–1), in the heart (50.0ng·mg^–1·min^–1), brown adipose tissue (157.2 ng·mg^–1·min^–1), and skin (10.0 ng·mg^–1·min^–1). White adipose tissue, brain and gut were not affected. Mild insulin treatment with persistent hyperglycaemia was not able to significantly ameliorate glucose disposal (14.5±0.9 mg·kg^–1·min^–1) or the glucose utilization index of most individual tissues (muscle=18.4; heart=36.2; brown adipose tissue=148.0; skin=7.7 ng· mg^–1· min^–1). These data show that correction of hyperglycaemia in streptozotocin-diabetic rats normalizes insulin action, while partial correction of the hypoinsulinaemia fails to do so.     

In vivo insulin resistance in streptozotocin-diabetic rats — evidence for reversal following oral vanadate treatment

Summary Hepatic glucose production and peripheral glucose utilisation were measured in vivo with the euglycaemic-hyper-insulinaemic clamp technique in rats rendered severely diabetic with streptozotocin (45 mg/kg) and in control rats. The rats were studied in the post-absorptive state while anaesthetised. The basal glucose production and glucose utilisation were significantly higher (p<0.001) in diabetic rats 9 days after streptozotocin administration. During the clamp studies, suppression of glucose production by the liver induced by submaximal or maximal insulin levels was significantly less (p<0.01 and p<0.001 respectively) effective in diabetic rats as compared to control rats. Glucose utilisation was significantly lower following both submaximal (p<0.01) or maximal (p<0.001) hyperinsulinaemia as compared to control rats. Oral administration of vanadate (0.2mg/ml in drinking water) for a 20-day period in diabetic rats lowered their plasma glucose levels to normal near values within 4 days, normalised plasma insulin levels, and increased pancreatic insulin stores. The rate of glucose disappearance (K value) and in vivo glucose-induced insulin secretion as estimated during an i.v. glucose tolerance test were not significantly improved. In control rats, vanadate treatment did not significantly affect any of the above parameters. In vanadate treated diabetic rats, basal glucose production was normalised. Following submaximal or maximal hyperinsulinaemia, glucose production was suppressed normaly. Basal glucose utilisation was restored and returned to normal values during submaximal hyperinsulinaemia. However, during maximal hyperinsulinaemia, glucose utilisation still remained significantly lower (p<0.05) as compared to vanadate-treated control rats. Vanadate treatment in control rats did not affect significantly any of the above parameters. These results show an insulin-like effect of vanadate upon glucose metabolism in vivo in the liver and peripheral tissues of diabetic rats, leading to normalisation of glycaemia in the absence of any significant improvement of insulin secretion.     

Subcutaneous versus intraperitoneal administration of insulin on post-prandial hyperglycaemia and glucose turnover in alloxan diabetic dogs

Summary The effects of subcutaneous and intraperitoneal insulin delivery by a closed-loop insulin infusion device on post-prandial hyperglycaemia and rates of glucose appearance and disappearance were compared in alloxan diabetic dogs. No differences in basal or post-prandial values or patterns of response were observed between the two routes of insulin delivery. In addition, the amounts of insulin infused and the plasma insulin concentrations achieved were not different for the two routes of insulin administration. These studies demonstrate that in the dog there appears to be no difference in the pattern of disposal of glucose from a mixed meal when insulin was administered intraperitoneally or subcutaneously at the rates of insulin infusion used in these experiments. Key words: Subcutaneous insulin, intraperitoneal insulin, glucose turnover, diabetic dogs.     

Acute and chronic effects of hyperglycaemia on glucose metabolism

Summary In normal man, several hormonal and metabolic adjustments allow the maintenance of the blood glucose concentration within narrow limits. Hyperglycaemia participates in this regulation via stimulation of glucose disposal and inhibition of glucose production. The effects are mediated, in addition to changes in insulin and glucagon secretion, by the mass-action effect of glucose. In both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients, hyperglycaemia, by mass-action abnormally elevates the basal glucose utilization rate but compensates for reduced postprandial insulin-stimulated glucose disposal. When exposed to chronic hyperglycaemia, the body tissues seem to protect themselves, at least partly, against excessive glucose utilization. These protective mechanisms include both a reduction in insulin stimulated glucose disposal and insulin secretion. Chronic hyperglycaemia may also reduce non-insulin-dependent glucose utilization, at least in rats. In Type 1 diabetic patients with normal peripheral insulin concentrations, chronic hyperglycaemia per se could be a major cause of insulin resistance. In Type 2 diabetic patients, insulin resistance is often already present before the development of overt fasting hyperglycaemia. At the diabetic stage, hyperglycaemia could, however, maintain a self-perpetuating cycle, where the deleterious effects of high glucose concentrations on insulin action and secretion cause further deterioration of glycaemic control. The biochemical basis for hyperglycaemia-induced insulin resistance is still far from clear, but could involve changes in the glucose transporter number and gene expression.     

Pancreatic hormones in streptozotocin-diabetic rats

Summary Pancreatic polypeptide (PP) levels of plasma and pancreas were studied in the rat after streptozotocin (STZ) injection. In 4 weeks of observation, plasma PP was elevated up to 4 times the control values with marked hyperglycemia and insulinopenia. At 4 weeks, intravenous (i.v.) glucose tolerance tests and i.v. insulin tolerance tests were performed. In the glucose tolerance test, control rats responded with a 10-fold increase in plasma insulin and 15% decrease in plasma PP levels, whereas STZ-diabetic rats produced no increase of plasma insulin and an approximately 50% reduction of plasma PP levels with marked hyperglycemia. In the insulin tolerance test, diabetic rats showed a marked increase in plasma PP levels and less increase in plasma insulin levels than the controls. In diabetic rats, pancreatic insulin levels were reduced to about 3.5% of control, whereas those of somatostatin (SRIF), PP and glucagon were elevated to 8.3, 2.7 and 1.4 times control, respectively. In a morphometric study, islet areas of diabetic rats were seen to be reduced to about 10% of control. With in vitro perfused pancreatic slices, STZ-diabetic pancreas released much more glucagon and PP than control pancreas. Thus, STZ injection in the rat caused marked β-cell damage as well as hyperplasia of SRIF, PP and glucagon cells, with glucagon and PP hypersecretion.     

Relationship between glucose tolerance,insulin secretion,and insulin action in non-obese individuals with varying degrees of glucose tolerance

Summary Plasma glucose and insulin concentration following a 75 g oral glucose challenge and glucose uptake during a hyperinsulinaemic glucose clamp study were determined in 50 non-obese individuals. The study population was divided into five groups on the basis of their glucose tolerance: normal, impaired glucose tolerance, Type 2 (non-insulin-dependent) diabetes mellitus with fasting plasma glucose of less than 8 mmol/l, between 8–15 mmol/l, and more than 15 mmol/l. The plasma insulin response was significantly greater (p<0.001) than normal in those with either impaired glucose tolerance or Type 2 diabetes and a fasting plasma glucose concentration less than 8 mmol/l. In contrast, the plasma insulin response was similar to normal in the other two groups of patients with Type 2 diabetes, i.e. fasting plasma glucose concentration 8–15 mmol/l or greater than 15 mmol/l. Glucose uptake rates were significantly lower (p<0.001) than normal in subjects with impaired glucose tolerance and all three groups of patients with Type 2 diabetes. Although glucose uptake rates during the glucose clamp studies were relatively similar in all four groups of glucose intolerant subjects, the values were significantly lower in those patients with Type 2 diabetes who had a fasting plasma glucose concentration greater than 8 mmol/l (p<0.01), These data indicate that a significant degree of insulin resistance exists in patients with impaired glucose tolerance or Type 2 diabetes, relatively independent of fasting plasma glucose concentration. Indeed, glucose uptake during glucose clamp studies fell 8-fold over a range in fasting plasma glucose concentration of from 4.5 to 6.5 mmol/l. In contrast, the plasma insulin response increased over the same range of fasting plasma glucose concentrations. The fact that this defect in insulin action can be seen in patients who are hyperinsulinaemic, not hypoinsulinaemic, and only modestly hyperglycaemic, is consistent with the hypothesis that resistance to insulin-stimulate glucose uptake is a basic characteristic of patients with impaired glucose tolerance or Type 2 diabetes.     

Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia

Summary Microvascular hyperaemia is decreased in subjects at risk of developing non-insulin-dependent diabetes mellitus (NIDDM) who have fasting hyperglycaemia. Such microvascular abnormalities may be involved in the pathogenesis of diabetic microangiopathy. To investigate the relationship of reduced microvascular hyperaemia to metabolic and blood pressure abnormalities associated with the prediabetic state, we studied 24 subjects with fasting hyperglycaemia and 24 age- and sex-matched control subjects. The microvascular hyperaemic response to local heating of the skin on the dorsum of the foot measured by laser Doppler fluximetry was reduced in the subjects with fasting hyperglycaemia (1.18 [0.87–1.83] volts vs 1.51 [1.30–2.14] volts normal subjects; p = 0.0002) and was negatively correlated with fasting plasma insulin concentration (R _s = −0.70; p = 0.001) and positively related to insulin sensitivity determined by continuous infusion of glucose with model assessment (CIGMA) (R _s = 0.52; p = 0.01), but showed no association with fasting plasma glucose, beta-cell function, 24 h ambulatory blood pressure profiles or serum lipid concentrations. These results suggest that hyperinsulinaemia, as a result of insulin resistance, may have a detrimental effect on microvascular function in the prediabetic state. [Diabetologia (1997) 40: 238–243] Received: 24 June 1996 and in final revised form: 11 November 1996     

The insulin sensitivity, glucose sensitivity, and acute insulin response to glucose load in adolescent type 2 diabetes in Taiwanese

BACKGROUND: Insulin sensitivity (SI), glucose sensitivity (SG), acute insulin response to glucose load (AIR), and obesity in adolescent type 2 diabetes patients (young diabetes, YDM) in Taiwan were studied. METHODS: Forty patients diagnosed at <22 years of age were enrolled and divided into non-obese (NOYDM, BMI < 27 kg/m(2)) and obese groups (OBYDM BMI > 27 kg/m(2)). Adult-onset type 2 diabetes patients (ADM) >40 years old (n = 41) and nondiabetic young adults (N) (n = 23) served as controls. Fasting plasma lipids, insulin, and glucose were measured. Homeostasis model assessment was calculated to estimate insulin sensitivity and beta-cell function. A frequent-sampled intravenous glucose tolerance test was performed to evaluate SI, SG, and AIR. RESULTS: SI and AIR were significantly lower in YDM and ADM than in N (0.92 +/- 0.13, 0.8 +/- 0.15 and 3.24 +/- 0.47 x 10(-4)/U/mL for SI; 40.3 +/- 20.3, 107.3 +/- 50.2, 1208 +/- 306.3 uU/min for AIR). SG of YDM and ADM were lower compared with N (0.014 +/- 0.00138, 0.0292 +/- 0.0058 vs 0.034 +/- 0.0086 min(-1) respectively). No difference was noted between YDM and ADM. SI and SG were not different in NOYDM and OBYDM. AIR was higher in OBYDM (83.6 +/- 34.3 vs -7.6 +/- 13.66 uU/min). CONCLUSIONS: YDM had defects in SI, SG, and AIR compared to N, which was similar to the pathophysiology of ADM. The results imply that YDM may be either a different subtype of diabetes or the same type of diabetes as ADM, with severe defects associated with earlier age of onset. OBYDM had higher AIR than NOYDM.     

Altered methionine metabolism in streptozotocin-diabetic rats

Summary We examined the origin of hypermethioninaemia in streptozotocin-diabetic rats. In rats administered streptozotocin over a range from 55 to 75 mg/kg, the dose of drug injected correlated directly with the plasma methionine concentration and inversely with the plasma insulin level. Although insulin administration prevented hypermethioninaemia in streptozotocin-diabetic rats, discontinuing insulin treatment resulted in a time-dependent increase in the plasma methionine level. Plasma methionine concentration was, however, normal in insulin-deprived BB Wistar rats despite severe hyperglycaemia. Thus, although insulin deficiency may be a contributing factor, it does not cause hypermethioninaemia independent of other drug-related effects. Administering a loading dose of methionine (100 mg/kg) indicated that streptozotocin-diabetic rats have a reduced metabolic capacity. Since dietary intake is the primary source of methionine, it is likely that hyperphagia combined with limited disposal produces hypermethioninaemia. Methionine is the most toxic amino-acid; therefore, metabolic studies using the streptozotocin model of insulin deficiency must be interpreted with caution.     

Pulsatile intravenous insulin replacement in streptozotocin-diabetic rats is more efficient than continuous delivery: effects on glycaemic control,insulin-mediated glucose metabolism and lipolysis

Summary Short-term exposure of tissues to pulses of insulin generally leads to an enhancement of insulin action. We have investigated the possible beneficial effects of long-term near-physiological continuous vs pulsatile intravenous insulin treatment of insulin-deficient streptozotocin (70 mg/kg) diabetic rats on blood glucose control, in vivo insulin action and in vitro insulin action in isolated adipocytes. First, we determined the 24-h peripheral plasma insulin profiles in normal rats under precisely controlled meal-feeding conditions. Basal plasma insulin levels (40±9 U/ml) oscillate with a periodicity of 11.9±0.9 min (p<0.05), and an amplitude of 60±10%. Subsequently, the 24-h insulin profile was mimicked in diabetic (D) rats by a continuous (c) or pulsatile (p) (6-min double, 6-min off) insulin infusion rate for 2 weeks, using a programmable pump-swivel unit. Control (C) rats received vehicle treatment. In Cc, Dc, Cp and Dp daily urinary glucose loss and average plasma glucose levels were 0±0, 7.5±4.4, 0±0, 0.8±0.4 mmol and 6.7±0.2, 11.5±2.7, 6.6±0.1, 5.9±1.4 mmol/l, respectively. Hypoglycaemia (<3 mmol/l) was observed in 10 and 20% of the blood samples collected from Dc and Dp rats, respectively. After 2 weeks of treatment, in vivo peripheral and hepatic insulin action was measured by the hyperinsulinaemic euglycaemic (6 mmol/l) clampwith[3-³H]-glucoseinfusion. Pre-clampcounter-regulatory hormone levels were similar among rats. Compared to Cc and Cp, Dc showed a reduction in insulin sensitivity and responsiveness for peripheral glucose uptake whereas Dp only showed a reduction in insulin sensitivity. Suppression of hepatic glucose production by insulin was similar among rats. After 2.5 weeks of treatment, epididymal adipocytes were isolated. Specific [¹²⁵I]-insulin binding, basal and insulin-stimulated [U-¹⁴C]-glucose uptake and isoproterenol-stimulated glycerol output were comparable among rat adipocytes. The inhibition of glycerol output by insulin was identical in Cp and Dp (V_max=48.6±6.1 and 42.3±4.6%) but blunted in Dc vs Cc (V_max=8.2±4.6 vs 44.0±7.2%, p<0.01) adipocytes, suggesting a post-binding defect in the antilipolytic action of insulin in Dc rats. In conclusion, long-term near-physiological pulsatile intravenous insulin replacement in insulin-deficient diabetic rats is more efficient than continuous delivery in reducing blood glucose, lowering glucosuria, increasing insulin sensitivity and inhibiting lipolysis.Abbreviations IDDM Insulin-dependent diabetes mellitus - AUC area under the curve - CV coefficient of variation     

The relationships between thyroid-stimulating hormone level and insulin resistance,glucose effectiveness,first- and second-phase insulin secretion in Chinese populations

Increased insulin resistance (IR); decreased glucose effectiveness (GE); and both first-and second phase of insulin secretion (FPIS, SPIS) have always been important factors for the development of type 2 diabetes. Therefore, in this study, we evaluated the relationships between thyroid-stimulating hormone (TSH) and these 4 factors in adult Chinese.We randomly enrolled 24,407 men and 24,889 women between 30 and 59 years old. IR, FPIS, SPIS and GE were measured with the equations built by our group.

• IR = log (1.439 + 0.018 × sex - 0.003 × age + 0.029 × BMI - 0.001 × SBP + 0.006 × DBP + 0.049 × TG - 0.046 × HDLC - 0.0116 × FPG) × 10 ^3.333
• FPIS = 10 [1.477 - 0.119 × FPG + 0.079 × BMI - 0.523 × HDLC]
• SPIS = 10 [-2.4 - 0.088 × FPG + 0.072 × BMI]
• GE = (29.196 - 0.103 × age - 2.722 × TG - 0.592 × FPG) ×10 ⁻³

The t test was performed to evaluate the differences between normal and diabetic groups. To evaluate the differences of the mean values of the 4 groups, from the highest to the lowest levels of TSH, we used a one-way analysis of variance.Age, high density lipoprotein-cholesterol and GE were higher in women. On the other hand, body mass index, blood pressure, low density lipoprotein-cholesterol, triglyceride, FPIS, SPIS and IR were higher in men. TSH was positively related to IR, FPIS, and SPIS and negatively related to GE. According to the r values, the tightest relationship was between TSH and IR, followed by GE, FPIS and SPIS.In conclusion, our data showed that IR, FPIS, and SPIS were positively related to the TSH level in middle-aged Chinese, whereas GE was negatively related. In both genders, IR had the tightest association followed by GE, FPIS, and SPIS.     

In vivo insulin resistance during pregnancy in the rat

Summary The glucose disappearance rate measured after IV glucose injection (1 g/kg body wt) remained unchanged between 12 and 21 day of gestation in the rat. In contrast, insulin secretion in response to IV glucose was markedly increased on day 19 and 21 of pregnancy, suggesting resistance to endogenous insulin. Glucose kinetics (glucose production, utilization and clearance) in response to various doses of IV insulin have been studied in anaesthetised postabsorbtive 19 day pregnant and virgin rats using 6-³H glucose. With the supramaximal dose of insulin (4 U/kg body wt) no differences in glucose kinetics were found between pregnant and virgin rats. In contrast, with the two lower doses of insulin (0.15 and 0.05 U/kg body wt) glucose production was inhibited by 36±3% and 13±2% (Mean±SEM) respectively in virgin rats, but was not decreased in pregnant rats. When the effect of insulin on glucose clearance was expressed as % of the maximal effect obtained with 4 U/kg body weight, the rise in glucose clearance in response to the two lower doses of insulin (0.15 and 0.05 U/kg body wt) was lower in pregnant (57.5±6 and 27.4±4%) than in virgin rats (73.3±6 and 42.2±7%). These results suggest that a decreased sensitivity to insulin appears in late pregnancy in the rat and could involve both liver and skeletal muscle.     

Comparison of portal and peripheral insulin delivery on carbohydrate metabolism in streptozotocin-diabetic rats

Summary Severely diabetic rats (150 mg streptozotocin/kg) were transplanted with fetal pancreatic islets: (a) under the kidney capsule to model peripheral insulin delivery, and (b) into the splenic pulp to model portal delivery. Long-term normoglycaemia, normal weight gain and normal peripheral insulin levels were achieved in both groups of transplanted animals. In both groups, 24-h fasted blood lactate, pyruvate and alanine were identical to those observed in sham-operated control animals. Blood glucose and plasma insulin responses to 300 mg oral glucose 8 weeks after transplantation were the same as in control animals. Hepatic glycogen concentration was, however, lower in fed rats with islets beneath the kidney capsule compared with control rats (p<0.01), suggesting inadequate hepatic insulinisation in the fed state with peripheral insulin delivery. Muscle glycogen was the same as in controls. Glucose turnover and glucose carbon recycling were not significantly different from results in normal control and splenic pulp islet-transplanted animals. The findings indicate that consistent normoglycaemia, normal glucose flux and normalisation of blood intermediary metabolites can be achieved in the rat with peripheral insulin delivery without associated hyperinsulinaemia.     

Control of blood glucose levels in the streptozotocin diabetic rat using a long-acting heat-treated insulin

Summary Diurnal plasma glucose levels have been studied two hourly in streptozotocin diabetic rats during insulin treatment. Protamine Zinc Insulin induced a very steep fall in plasma glucose level from 359±100 (SD) mg/100 ml to 91± 49 mg/100 ml within two hours. Plasma glucose was then low (13–60 mg/100 ml) until after 18 hours when an equally steep rise in glucose concentration ocurred. Six other insulin preparations and several insulin treatment regimens were tested with the aim of normalising the 24 hour plasma glucose profile of streptozotocin diabetic rats. One preparation, a non-commercial, very long acting Ultralente NOVO (Mc, ox pH 5.5) yielded a diurnal plasma glucose profile reasonably close to normal when it was administered once a day and when the dose was based on daily blood glucose measurements. Mean plasma glucose was 122±55 mg/100 ml with a nadir of 55±15 and a maximal of 187±99 mg/100 ml.     

Assessment of abnormal glucose homeostasis and insulin resistance in Turkish obese children and adolescents

BACKGROUND: The worldwide increase in the prevalence of childhood obesity is reaching epidemic proportions and is associated with a dramatic rise in cases of type 2 diabetes. We determined the prevalence of impaired glucose regulation and insulin resistance in obese children and adolescents. METHODS: A total of 196 obese children [SD score (SDS) of body mass index (BMI): 2.17 +/- 0.03], aged 7-18 years, including 86 male subjects, underwent an oral glucose tolerance test (1.75 g glucose/kg body weight). We used the modified WHO criteria adapted for children for abnormal glucose homeostasis. Homeostasis model assessment was used to estimate insulin resistance in all subjects. The insulin sensitivity index was also determined in subjects. RESULTS: Of the total of 196 obese children, 15 (6.6%) had an abnormal fasting glucose level. Of the 196 obese children, 35 (18%) had impaired glucose tolerance (IGT) and 83 (43%) had insulin resistance. Of the 196 obese children were six (3%) diagnosed with type 2 diabetes. Insulin resistance indices were correlated well with the degree of abnormal glucose tolerance. CONCLUSIONS: IGT, insulin resistance and type 2 diabetes are far more common in obese Turkish children than previously thought. Early treatment in obese children and adolescents with IGT constitutes a strategy of reversing the progression to beta-cell failure and preventing type 2 diabetes.     

Mechanism of action of insulin and insulin analogues

Summary A [¹⁴C]-glucose tracer infusion method was used to compare the effects of insulin infusion on glucose metabolism with the effects of infusion of three semisynthetic modified insulins and of proinsulin. Insulin produced hypoglycaemia in the anaesthetised dog by decreasing hepatic glucose production and increasing peripheral glucose utilisation. Compensatory antihypoglycaemic mechanisms eventually modified these responses. A₁ B₂₉-Diacetyl insulin exerted an hypoglycaemic effect entirely by stimulation of peripheral glucose uptake. A₁-B₂₉ crosslinked insulins and proinsulin produced hypoglycaemia almost entirely by decreasing hepatic glucose production and had little effect on tissue uptake. These observations suggest that insulin analogues may have actions in vivo that are qualitatively different from those of native insulin and suggest that certain analogues have a predominant action on the liver. This has important therapeutic implications concerning the development of semisynthetic insulins for clinical use.     

Relative contribution of glycogenolysis and gluconeogenesis to hepatic glucose production in control and diabetic rats. A re-examination in the presence of euglycaemia

Summary Several studies have suggested that, in non-insulin-dependent diabetes mellitus, augmented gluconeogenesis is responsible for increased endogenous glucose production (EGP) and in the end determines fasting hyperglycaemia. However, human and animal studies have been conducted by comparing euglycaemic control subjects to hyperglycaemic diabetic probands. We measured EGP and hepatic gluconeogenesis comparing control and diabetic rats in the fasting state (with diabetic animals in hyperglycaemia), re-examining them in the presence of identical euglycaemia (with diabetic rats made acutely euglycaemic through i. v. phloridzin) or during a hyperinsulinaemic clamp. All rats were infused with [3-³H]-glucose and [U-¹⁴C]-lactate; the ratio between ¹⁴C-uridine-diphosphoglucose (reflecting ¹⁴C-glucose 6-phosphate) and 2 ·¹⁴C-phosphoenolpyruvate specific activities (both purified by high performance liquid chromatography from liver) measured hepatic gluconeogenesis. In diabetic animals, although overall EGP ( ∼ 19.5 mg · kg^–1· min^–1) remained unaffected by experimental euglycaemia, the contribution of glycogenolysis largely increased (from 5.4 to 11.7 mg · kg^–1· min^–1, hyper- vs euglycaemia) while gluconeogenesis decreased (from 14.0 to 8.1 mg · kg^–1? min^–1); both were responsible for the augmented EGP (control rats, EGP: 12.7 mg · kg^–1· min^–1; gluconeogenesis: 5.9 mg · kg^–1· min^–1; glycogenolysis: 6.7 mg · kg^–1· min^–1). Finally, during insulin clamp, gluconeogenesis and glycogenolysis were similarly decreased, and both contributed to the hepatic insulin-resistance of diabetic animals. We conclude that, in this model of non-insulin-dependent diabetes, augmented gluconeogenesis is not primarily responsible for fasting hyperglycaemia and hepatic insulin resistance. Finally, failure to accurately match the experimental conditions in which diabetic and control humans or animals are compared affects gluconeogenesis, overestimating its role in determining hyperglycaemia. [Diabetologia (1998) 41: 307–314] Received: 10 September 1997 and in revised form: 13 November 1997     

Enhanced hepatic insulin sensitivity,but peripheral insulin resistance in patients with Type 1 (insulin-dependent) diabetes

Summary Sensitivity to insulin in vivo was studied in 8 normal weight C-peptide negative Type 1 (insulin-dependent) diabetic patients (age 23±1 years, diabetes duration 6±2 years), and in 8 age, weight and sex matched healthy subjects, using the euglycaemic clamp and 3-³H-glucose tracer technique. Prior to the study diabetic patients were maintained normoglycaemic overnight by a glucose controlled insulin infusion. Sequential infusions of insulin in 3 periods of 2 h resulted in mean steady state insulin levels of 12±2 versus 11±1, 18±2 versus 18±2 and 28±3 versus 24±2 U/ml in diabetic patients and control subjects. Corresponding glucose utilization rates were 2.4±0.2 versus 2.4±0.1, 2.4±0.2 versus 3.0±0.3 and 2.9±0.3 versus 4.6±O.6 mg·kg^–1·min^–1, p<0.02. Portal insulin values in the three periods were calculated to 12±2 versus 25±3, 18±2 versus 32±3 and 28±3 versus 37±3 U/ml in the diabetic patients and control subjects using peripheral insulin and C-peptide concentrations and assuming a portal to peripheral insulin concentration gradient of 1 in diabetic patients and of 2.4 in control subjects. Corresponding glucose production rates were 2.5±0.2 versus 2.4±0.1, 1.6±0.1 versus 0.9±0.2 and 0.7±0.1 versus 0.4±0.2 mg·kg^–1·min^–1. Using this approach the insulin dose-response curve for the peripheral glucose utilization was right-ward shifted, while the dose-response curve for the hepatic glucose production as a function of portal insulin levels was left-ward shifted. We conclude that in vivo insulin action is increased in the liver but decreased in peripheral tissues in insulin treated Type 1 diabetic patients. Presumably these oppositely directed changes in insulin action are acquired defects, secondary to the present mode of peripheral insulin treatment.     

Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance

AIM: The second-generation thiazolidinediones (TZDs), rosiglitazone and pioglitazone, significantly decrease fasting plasma glucose and glycosylated haemoglobin (HbA(1c)) levels in patients with diabetes. Recent studies suggest that early treatment with TZDs may prevent the progression from insulin resistance (IR) to type 2 diabetes mellitus (T2DM). This prospective analysis examined the effect of early TZD treatment in the prevention or delay of T2DM in a multiethnic population with impaired glucose tolerance (IGT) and IR. METHODS: The analysis included 172 patients (aged 29-86 years) with IGT and IR (normal or borderline HbA(1c), C-peptide levels > 2 mg/ml, fasting blood sugar 100-125 mg/dl, and 2-h postprandial blood glucose levels 140-200 mg/dl). Patients in the active treatment group (n = 101) had received troglitazone for an average of 10 months before being randomly switched to rosiglitazone (4 mg/day) or pioglitazone (30 mg/day). Patients were switched when troglitazone was withdrawn from the US market because of liver toxicity concerns. Patients with IGT and IR who received no antidiabetic medication served as a control group (n = 71). HbA(1c) and C-peptide levels were measured at baseline (2 years) and study end point (3 years). Kaplan-Meier testing, using time to outcome as the main outcome variable, determined risk reduction in the TZD group relative to the control group. RESULTS: Mean HbA(1c) and C-peptide levels decreased for patients receiving either TZD at the 2-year assessment, and reductions were maintained at study end point. After 2 years, none of the patients receiving TZD therapy progressed to T2DM; three patients progressed to T2DM by study end point. In the control group, 11 patients became diabetic after 2 years and 19 patients became diabetic by the end of the study. The incidence (risk reduction) of diabetes after 3 years was 88.9% lower in the TZD group compared with the control group (p < 0.001). CONCLUSIONS: The TZDs, rosiglitazone and pioglitazone, were effective in reducing HbA(1c) and C-peptide levels in patients with IGT/IR. Progression of IR/IGT to T2DM appears to be significantly delayed or prevented with early TZD treatment.