Fasting and feeding variations of insulin requirements and insulin binding to erythrocytes at different times of the day in insulin dependent diabetics--assessed under the condition of glucose-controlled insulin infusion

Nine insulin-dependent diabetic patients were examined for insulin requirement, counterregulatory hormones, and receptor binding during their connection to glucose-controlled insulin infusion system. They were of 103% ideal body weight. A diet of 45% carbohydrate, 20% protein and 35% fat was divided into three meals and three snacks averaging the daily calorie intake of 1859 kcal. Following an equilibrating phase of 14 hours after the connection to the glucose-controlled insulin infusion system the blood samples were taken at 0800, 1200 and 1800. The insulin infusion rate increased at 0300 in the early morning from 0.128 mU/kg/min to 0.221 mU/kg/min (P less than 0.02). The postprandial insulin infusion rate jumped from 0.7 U/h (0700-0800) to 7.5 U/h (0800-0900). The calorie related and carbohydrate related insulin demands after breakfast were also highest and declined after lunch respectively (1.16 uU/kg/min kj vs. 0.61 uU/kg/min kj, P less than 0.05 and 236 mU/g CHO vs. 129 mU/g CHO and 143 mU/g CHO). Of the counterregulatory hormones the cortisol showed a significant diurnal rhythm to insulin demands. The insulin tracer binding was higher at 0800 before breakfast than that at 1200 before lunch (P less than 0.05). The increased binding could be better attributed to receptor concentration change than to affinity change. The cause of insulin relative insensitivity in the morning could be due to altered liver response to the cortisol peak in type 1 diabetics. The preserved variation of insulin binding in our patients might be referred to feeding.     

WITHDRAWN: Expression of p53, p63, and p73 isoforms in squamous cell carcinoma and adenocarcinoma of esophagus☆,☆☆

Diabetic microangiopathy is often observed in diabetic patients, but there is little evidence regarding the relationship between post-prandial glycemia or insulinemia and the incidence of diabetic microangiopathy. In this study, to elucidate the relationship between post-prandial glycemia (or insulinemia) and diabetic microangiopathy, we performed a cross-sectional study of 232 subjects with type 2 diabetes mellitus who were not being treated with insulin injections. A multiple regression analysis showed that post-prandial hyperglycemia independently correlated with the incidence of diabetic retinopathy and neuropathy. Post-prandial hyperglycemia also correlated, although not independently, with the incidence of diabetic nephropathy. In addition, interestingly, post-prandial hypoinsulinemia independently correlated with the incidence of diabetic retinopathy, although not correlated with diabetic neuropathy or nephropathy. In conclusion, post-prandial hyperglycemia, rather than fasting glycemia or hemoglobin A1c levels, is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients.     

Metabolic and hormonal effects of test meals with various protein contents in pigs

The postprandial release of immunoreactive insulin, glucagon, gastrin, somatostatin, pancreatic polypeptide (PP), and gastric inhibitory polypeptide (GIP) was studied in parallel with the absorption of sugars and amino acids in conscious pigs. Six pigs fitted with permanent catheters in the portal vein and arterial blood system as well as within an electromagnetic flow probe around the portal vein received successively at 3-day intervals, three meals of 800 g each containing 0, 14, or 28% protein (semisynthetic diets based on fish protein). Blood samples were collected and portal blood flow was recorded during a postprandial period of 8 h. For the same level of feed intake, an increase in the dietary protein concentration led to a higher alpha-amino nitrogen absorption and to a lower appearance of reducing sugars in the portal vein; in addition, the carbohydrate absorption efficiency (amounts absorbed as a percentage of amounts ingested) was reduced, showing the competition between the absorption of amino acids and glucose. The largest absorption occurred during the first 4 h after the meal, but neither the digestion of proteins nor that of carbohydrates were finished 8 h after the meal since portoarterial differences could still be observed. All test meals induced a rise of portal and peripheral concentrations of insulin, gastrin, somatostatin, and PP, and of the systemic level of GIP. Glucagon increased after the 28% protein meal only. The rise of plasma insulin paralleled that of blood glucose, and bore a significant positive relationship to the systemic GIP level in the early postprandial period. In terms of absolute amounts, portoarterial concentration gradients increased postprandially. Insulin release was significantly the highest after intake of the 14% protein diet. The gastrin response was significantly correlated to the amount of protein. Similarly the release of glucagon and somatostatin tended to increase with increasing dietary amount, but differences failed to reach significance (P less than 0.05), except for glucagon 2 h after the meal. There were very close relationships between the hourly amounts of alpha-amino nitrogen absorbed and gastrin and glucagon production, as between insulin and PP secretions. From the present results, the induction of physiological increments of plasma peptide concentration in 60-kg pigs would require infusion rates of about 50-250 micrograms/h for insulin, 1-4 micrograms/h for gastrin 17, 5-10 micrograms/h for glucagon and somatostatin, and 5-50 micrograms/h for PP.     

Carbohydrates modulate opiate receptor mediated mechanisms during postprandial endocrine function

The present study was designed to determine the role of carbohydrates during naloxone-induced opiate receptor blockade upon the postprandial rise of plasma somatostatin (SLI), insulin and pancreatic polypeptide (PP) levels in response to protein and fat test meals in conscious dogs. Test meals consisting of 50 g liver extract + 50 g sucrose or 50 g corn oil + 50 g sucrose dissolved in 300 ml water were instilled intragastrically, respectively. Additionally, liver extract and fat meals were given with a concomitant intravenous infusion of glucose. To all test meals either naloxone (4 mg) or saline was added. The addition of sucrose to liver extract or the infusion of i.v. glucose during the liver meal abolished the inhibitory effect of naloxone on the rise of postprandial somatostatin levels which has been described recently. The addition of carbohydrate either orally or intravenously to the fat meal resulted in an even stimulatory effect of naloxone upon the rise of postprandial somatostatin levels. Insulin levels were not changed during liver extract + sucrose or i.v. glucose, respectively. When sucrose or i.v. glucose was administered together with the fat meal the addition of naloxone augmented postprandial insulin secretion. Pancreatic polypeptide (PP) release was augmented during the combination of sucrose or i.v. glucose with the fat and liver meal when naloxone was present in the meals. The present data demonstrate that the addition of carbohydrates either orally or intravenously to fat and protein meals modulates the effect of endogenous opiates in the regulation of postprandial somatostatin, insulin and pancreatic polypeptide release in dogs in a way that carbohydrates induce inhibitory mechanisms that are mediated via endogenous opiate receptors.     

Effect of non-digestible gluco-oligosaccharides on glucose sensitivity in high fat diet fed mice

Non digestible dietary carbohydrates have been reported to modify lipaemia and post-prandial glycaemia and insulinaemia. The aim of this study was to investigate the effect of a non-digestible gluco-oligosaccharides (GOS) diet on glucose, insulin, triglycerides and free fatty acid blood levels and glucose sensitivity in high fat diet fed mice (a high fat diet composed of 45% fat, 35% carbohydrate and 20% protein). Female C57B16/J mice were divided into two groups fed a high fat diet (HF) for 20 weeks supplemented or not with 1.5 g/kg/day of GOS (HF-GOS). The GOS supplementation did not change body weight nor fat pad mass, nor any of the blood parameters measured (glucose, insulin, leptin, triglycerides, and free fatty acids). However, mice which received the GOS supplemented diet showed an increased glucose utilization after a 1 g/kg load of glucose compared with the mice fed the high fat diet alone. Our results suggest a role for non-digestible GOS in the regulation of carbohydrate metabolism.     

The effect of glucagon administration on protein synthesis in skeletal muscles, heart and liver in vivo.

Infusion of glucagon (0.5 mg/h per 100 g body wt.) into fed rats for 6 h inhibited protein synthesis in skeletal muscle, but not in heart. The order of sensitivity of three muscles was plantaris greater than gastrocnemius greater than soleus. Treatment with glucagon for periods of 1 h or less had no effect. Liver protein synthesis was inhibited by glucagon treatment for 10 min, but stimulated after 6 h. The effect of glucagon on muscle was not secondary to impaired food absorption or to depletion of amino acids by increased gluconeogenesis, since the inhibition of protein synthesis was observed in postabsorptive and amino acid-infused rats. The failure of glucagon to inhibit muscle protein synthesis after 1 h may have been caused by the increase in plasma insulin that occurred at this time, since an inhibition was detected in insulin-treated diabetic rats. The lowest infusion rate that gave a significant decrease in muscle protein synthesis was 6 micrograms/h per 100 g body wt., despite a small increase in plasma insulin. This gave plasma glucagon concentrations in the high pathophysiological range, suggesting that glucagon may be significant in the pathogenesis of muscle wasting in metabolic stresses such as diabetes and starvation.     

Carbohydrate- and lipid-enriched meals acutely disrupt glycemic homeostasis by inducing transient insulin resistance in rats

Chronic intake of high-carbohydrate or high-lipid diets is a well-known insulin resistance inducer. This study investigates the immediate effect (1-6 h) of a carbohydrate- or lipid-enriched meal on insulin sensitivity. Fasted rats were refed with standard, carbohydrate-enriched (C), or lipid-enriched (L) meal. Plasma insulin, glucose, and non-esterified fatty acids (NEFA) were measured at 1, 2, 4, and 6 h of refeeding. The glucose-insulin index showed that either carbohydrates or lipids decreased insulin sensitivity at 2 h of refeeding. At this time point, insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) detected insulin resistance in C rats, while GTT confirmed it in L rats. Reduced glycogen and phosphorylated AKT and GSK3 content revealed hepatic insulin resistance in C rats. Reduced glucose uptake in skeletal muscle subjected to the fatty acid concentration that mimics the high NEFA level of L rats suggests insulin resistance in these animals is mainly in muscle. In conclusion, carbohydrate- or lipid-enriched meals acutely disrupt glycemic homeostasis, inducing a transient insulin resistance, which seems to involve liver and skeletal muscle, respectively. Thus, the insulin resistance observed when those types of diets are chronically consumed may be an evolution of repeated episodes of this transient insulin resistance.     

The individual and combined effects of glycemic index and protein on glycemic response, hunger, and energy intake

Although high protein and low glycemic index (GI) foods are thought to promote satiety, little is known about the effects of GI, protein, and their interaction on hunger and energy intake several hours following a mixed meal. This study investigated the long term effects of GI, protein, and their combined effects on glucose, insulin, hunger, and energy intake in healthy, sedentary, overweight, and obese adults (BMI of 30.9 ± 3.7 kg/m²). Sixteen individuals participated separately in four testing sessions after an overnight fast. The majority (75%) were non‐Hispanic Blacks. Each consumed one of four breakfast meals (high GI/low protein, high GI/high protein, low GI/low protein, low GI/high protein) in random order. Visual analog scales (VAS) and blood samples were taken at baseline, 15 min, and at 30 min intervals over 4 h following the meal. After 4 h, participants were given the opportunity to consume food ad libitum from a buffet style lunch. Meals containing low GI foods produced a smaller glucose (P < 0.002) and insulin (P = 0.0001) response than meals containing high GI foods. No main effects for protein or interactions between GI and protein were observed in glucose or insulin responses, respectively. The four meals had no differential effect on observed energy intake or self‐reported hunger, satiety, and prospective energy intake. Low GI meals produced the smallest postprandial increases in glucose and insulin. There were no effects for GI, protein, or their interaction on appetite or energy intake 4 h after breakfast.     

Feeding frequency has diet-dependent effects on plasma hormone concentrations but does not affect oocyte quality in dairy heifers fed fibre- or starch-based diets

The post-fertilisation developmental capacity of bovine oocytes recovered by ultrasound guided transvaginal follicular aspiration (ovum pick-up, OPU) is influenced by diet-induced changes in hormone and metabolite concentrations. The objectives of this experiment were first to determine whether post-prandial changes in hormone concentrations, induced by changing the frequency of feeding, influenced oocyte quality and second whether changes in plasma glucagon concentration were associated with oocyte quality. Using a 2 × 2 factorial design, Holstein heifers (six per treatment) were fed either fibre- or starch-based diets containing either 189 or 478 g starch/kg dry matter. The diets were offered in either two or four equal meals per day and supplied twice the maintenance energy requirement. Blood samples were obtained both at weekly intervals (three samples per heifer, collected before feeding) during the experiment and throughout an entire 24-h period (15 or 17 samples per heifer for twice or four times daily-fed heifers, respectively). Each heifer underwent six sessions of OPU (twice weekly) beginning 25 days after introduction of the diets. Oocyte quality was assessed by development to the blastocyst stage in synthetic oviductal fluid following in vitro fertilisation. Mean weekly plasma insulin concentrations did not differ between diets, but plasma glucagon concentrations were greatest when heifers were fed the starch-based diet twice daily compared with the other diets. When heifers were offered four meals per day, there were no meal-related changes in hormone concentrations. However, when heifers were offered two meals per day, plasma insulin concentration increased after feeding the starch-based, but not the fibre-based diet. Plasma glucagon concentration increased after meals when heifers were fed twice daily and the increase was substantially greater when the starch-based diet was fed. Treatments did not influence (overall mean with mean ± s.e.) ovarian follicle size distribution or oocyte recovery by OPU (6.2 ± 0.4 per heifer), the proportion of oocytes that cleaved following insemination (0.57 ± 0.030) or blastocyst yield (0.27 ± 0.027 of oocytes cleaved). In conclusion, by feeding diets differing in carbohydrate source at different frequencies of feeding, meal-related changes in plasma hormone profiles were altered significantly, but oocyte quality was not affected. Therefore effects of diet on oocyte quality appear not to be mediated by meal-related fluctuations in hormone concentrations.     

Response of hexokinase enzymes and the insulin system to dietary carbohydrates in the common carp, Cyprinus carpio

The response of the common carp to diets with varying amounts of digestible starch, provided either as pea meal (LP, HP, 30 and 46% peas, respectively) or as cereal (LW, HW, 30 and 46% wheat, respectively), was studied and compared with the response to a carbohydrate-free protein-rich diet (CF). Here we focused on the utilisation of dietary carbohydrates by examining the relationship between dietary starch intake, hepatic hexokinase activities, circulating insulin and muscle insulin receptor system. Plasma glucose concentration and hepatic high Km hexokinase (glucokinase, GK) activity were not affected by the content of digestible starch, but 6 h after feeding enzyme activity was higher in the fish fed carbohydrate diets. Similarly, low Km hexokinase (HK) activity was also higher in the fish 24 h after feeding. Fat gain and protein retention were significantly improved by increased digestible starch intake, especially in the HP group, which in turn, presented the highest plasma insulin levels. Glycogen stores were moderately increased by the ingestion of digestible starch. The number of insulin receptors was greater in the CF group than in fish on carbohydrates, except the HP group. Our results confirmed that the common carp uses dietary carbohydrates efficiently, especially when there are provided by peas. This efficiency might be related to the enhanced response of postprandial insulin observed in the HP group.     

Transdermal Delivery of Insulin by Amidated Pectin Hydrogel Matrix Patch in Streptozotocin-Induced Diabetic Rats: Effects on Some Selected Metabolic Parameters

Purpose

Studies in our laboratory are concerned with developing optional insulin delivery routes based on amidated pectin hydrogel matrix gel. We therefore investigated whether the application of pectin insulin (PI)-containing dermal patches of different insulin concentrations sustain controlled release of insulin into the bloodstream of streptozotocin (STZ)-induced diabetic rats with concomitant alleviation of diabetic symptoms in target tissues, most importantly, muscle and liver.

Methods

Oral glucose test (OGT) responses to PI dermal matrix patches (2.47, 3.99, 9.57, 16.80 µg/kg) prepared by dissolving pectin/insulin in deionised water and solidified with CaCl₂ were monitored in diabetic rats given a glucose load after an 18-h fast. Short-term (5 weeks) metabolic effects were assessed in animals treated thrice daily with PI patches 8 hours apart. Animals treated with drug-free pectin and insulin (175 µg/kg, sc) acted as untreated and treated positive controls, respectively. Blood, muscle and liver samples were collected for measurements of selected biochemical parameters.

Results

After 5 weeks, untreated diabetic rats exhibited hyperglycaemia and depleted hepatic and muscle glycogen concentrations. Compared to untreated STZ-induced diabetic animals, OGT responses of diabetic rats transdermally applied PI patches exhibited lower blood glucose levels whilst short-term treatments restored hepatic and muscle glycogen concentrations. Plasma insulin concentrations of untreated diabetic rats were low compared with control non-diabetic rats. All PI treatments elevated plasma insulin concentrations of diabetic rats although the levels induced by high doses (9.57 and 16.80 µg/kg) were greater than those caused by low doses (2.47 and 3.99 µg/kg) but comparable to those in sc insulin treated animals.

Conclusions

The data suggest that the PI hydrogel matrix patch can deliver physiologically relevant amounts of pharmacologically active insulin.

Novelty of the Work

A new method to administer insulin into the bloodstream via a skin patch which could have potential future applications in diabetes management is reported.     

Postprandial glucose, insulin and glucagon responses to meals with different nutrient compositions in non-insulin-dependent diabetes mellitus

Postprandial glycaemic and hormone responses to meals with different nutrient compositions and their heterogeneity were evaluated in 16 non-insulin-dependent diabetic patients and 5 healthy volunteers. Five kinds of nutrient stimulation--75 g glucose, a Japanese mixed meal (400 kcal, carbohydrate 60%, protein 14%, fat 26%), a high protein meal (300 kcal, C 26%, P 64%, F 10%), a high fat meal (300 kcal, C 23%, P 5%, F 72%) and 20 g iv glucose--was given to each subject. On the average, in both normal and diabetic subjects, the increases in plasma glucose (PG) and insulin (IRI) were the largest with the oral glucose load and the smallest with the high protein meal. The ratio of increase in IRI and PG (sigma delta IRI/sigma delta PG) was the highest with the high protein meal and the lowest with the oral glucose load. sigma delta IRI with the high protein meal and the high fat meal were the same in normal and diabetic subjects. However, each of the 16 NIDDM patients and 5 normal volunteers exhibited a different pattern of response to the nutrient stimuli and no definite subgroup could be classified. There was no correlation between metabolic responses and family history of diabetes mellitus, duration of diabetes, body mass index and fasting plasma glucose. The present results suggest the nearly intact capacity of insulin secretion in NIDDM in response to a high protein or high fat meal and the difficulty of subclassification in NIDDM according to the glycaemic and hormone responses to the different nutrient stimuli.     

Direct assessment of muscle glycogen storage after mixed meals in normal and type 2 diabetic subjects

To understand the day-to-day pathophysiology of impaired muscle glycogen storage in type 2 diabetes, glycogen concentrations were measured before and after the consumption of sequential mixed meals (breakfast: 190.5 g carbohydrate, 41.0 g fat, 28.8 g protein, 1253 kcal; lunch: 203.3 g carbohydrate, 48.1 g fat, 44.0 g protein, 1497.5 kcal) by use of natural abundance (13)C magnetic resonance spectroscopy. Subjects with diet-controlled type 2 diabetes (n = 9) and age- and body mass index-matched nondiabetic controls (n = 9) were studied. Mean fasting gastrocnemius glycogen concentration was significantly lower in the diabetic group (57.1 +/- 3.6 vs. 68.9 +/- 4.1 mmol/l; P < 0.05). After the first meal, mean glycogen concentration in the control group rose significantly from basal (97.1 +/- 7.0 mmol/l at 240 min; P = 0.005). After the second meal, the high level of muscle glycogen concentration in the control group was maintained, with a further rise to 108.0 +/- 11.6 mmol/l by 480 min. In the diabetic group, the postprandial rise was markedly lower than that of the control group (65.9 +/- 5.2 mmol/l at 240 min, P < 0.005, and 70.8 +/- 6.7 mmol/l at 480 min, P = 0.01) despite considerably greater serum insulin levels (752.0 +/- 109.0 vs. 372.3 +/- 78.2 pmol/l at 300 min, P = 0.013). This was associated with a significantly greater postprandial hyperglycemia (10.8 +/- 1.3 vs. 5.3 +/- 0.2 mmol/l at 240 min, P < 0.005). Basal muscle glycogen concentration correlated inversely with fasting blood glucose (r = -0.55, P < 0.02) and fasting serum insulin (r = -0.57, P < 0.02). The increment in muscle glycogen correlated with initial increment in serum insulin only in the control group (r = 0.87, P < 0.002). This study quantitates for the first time the subnormal basal muscle glycogen concentration and the inadequate glycogen storage after meals in type 2 diabetes.     

Ghrelin response to protein and carbohydrate meals in relation to food intake and glycerol levels in obese subjects

Obese subjects have lower basal and an attenuated decrease of postprandial plasma ghrelin following carbohydrate-rich meals, while the response to protein is unknown. Therefore, plasma ghrelin levels were examined after ingestion of satiating amounts of a protein- or carbohydrate-rich meal in relation to food and energy intake and hunger/satiety ratings in 30 obese subjects followed 240 min later by ad lib sandwiches. Food intake and hunger/satiety ratings were identical while energy intake was significantly greater after bread (861 +/- 62.7 vs. 441 +/- 50.4 kcal, p < 0.001). Second meal food and energy intake were not different. Ghrelin decreased after bread, but increased by 50 pg/ml (p < 0.001) after meat. The corresponding increase of insulin was 55 vs. 9 microU/ml (p < 0.001). Glycerol levels decreased significantly less after the protein meal compared to carbohydrates. After protein glycerol was significantly correlated to the rise of ghrelin but not insulin. These data demonstrate that, in obese subjects, protein has no different satiating effect than carbohydrate despite divergent ghrelin levels. Energy intake corresponds to energy density of the respective food items. Ghrelin response to both meals is qualitatively similar but quantitatively attenuated compared to normal weight subjects. The relationship between ghrelin and glycerol would support recent observations of a possible role of ghrelin in fat metabolism.     

A comparison of metformin versus guar in combination with sulphonylureas in the treatment of non insulin dependent diabetes

Twelve non-obese non insulin dependent diabetics whose mean +/- SE fasting blood glucose was 12.9 +/- 0.9 mmol/l despite maximal doses of sulphonylureas, received 8 weeks of guar (5 g tid before meals) and 8 weeks of metformin (0.5 g tid) following a six week washout period, in a cross-over design. Guar significantly lowered fasting cholesterol and triglyceride concentrations but did not alter glucose concentrations. Conversely, metformin significantly reduced fasting and post-prandial glucose concentrations but had no influence on plasma lipids.     

Muscle insulin binding and plasma levels in relation to liver glucokinase activity,glucose metabolism and dietary carbohydrates in rainbow trout

Rainbow trout were fed for 10 weeks with either a carbohydrate-free diet (C-free) or with four experimental diets containing various levels (20 or 40%) and sources of starch (extruded wheat or peas) in order to examine metabolic utilisation of dietary vegetable carbohydrates and its endocrine control. The study was focused on the parameters described as limiting in glucose metabolism in fish. Feeding trials were conducted at 8 and 18 degrees C to establish whether carbohydrate-rich diets can be used in trout farming irrespective of water temperature. At both temperatures, pea diets (especially the highest level) resulted in a feed efficiency as high as the C-free diet. Fish had similar growth rates except when fed the low wheat content diet. Glycaemia values 6 h after feeding were significantly higher in trout fed carbohydrate diets than those given the C-free diet, whereas plasma insulin levels were similar independently of the levels of dietary starch. This study provides the first evidence that glucokinase (GK) activity and mRNA level in trout liver increase in proportion to the content of dietary starch. Nevertheless, these changes were not correlated with plasma insulin levels. Insulin-like growth factor-I (IGF-I) binding and number of receptors in skeletal muscle were consistently higher than those for insulin but no diet-induced differences were found for any of these parameters. Temperature clearly affected the postprandial profile of glucose and insulin, which both showed lower levels 6 h after feeding at 8 degrees C than at 18 degrees C, which was consistent with a lower feed intake. Glucose and insulin levels decreased markedly 24 h after feeding at 18 degrees C, while they were still high at 8 degrees C, an observation concordant with delayed transit rate. These findings indicate satisfactory adaptation of rainbow trout to diets with a relatively high vegetable starch content, especially when provided as extruded peas, and indicate that diets with increased levels of carbohydrates can be used in this species even when it is reared at low temperature.     

Enhanced endogenous insulin secretion after treatment with monocomponent insulin

Eight maturity-onset diabetic patients who had no infections, liver diseases or other endocrine diseases which might affect carbohydrate metabolism were treated with monocomponent lente insulin, which is known to have little antigenicity, until blood sugar was controlled. The diurnal values of the blood sugar (BS) and immunoreactive insulin (IRI) were obtained before treatment and on the third day after the withdrawal of insulin treatment. One patient was dropped from the study because of insulin antibody formation. The total integrated IRI area in the diurnal profile was increased from 98.9 +/- 23.7 to 186.1 +/- 37.7 muU.h/ml (p less than 0.05), while the total blood sugar area was decreased from 7,500 +/- 1,200 to 5,510 +/- 1,214 mg-h% (p less than 0.05). Oral Glucose Tolerance Test on the fourth day after the withdrawal of insulin treatment showed increased IRI response compared to pretreatment. It is concluded that endogenous insulin secretion could be increased in the diabetic patient by the metabolic control with exogenous insulin injections.     

Insulin substitution: new insulins, new modes of delivery

The demonstrated role of the tight control of hyperglycaemia for the prevention of long-term diabetic complications has reoriented the goals of insulin supply toward the search for restoration of the effects of physiological insulin secretion rather than the simple survival of insulin deficient patients and the reduction in the number of daily insulin injections to be performed. Normal blood glucose control requires the availability of a fast-acting insulin therapy at meal time in order to reduce hyperglycaemic excursions and a basal insulin therapy able to stabilize blood glucose between meals. Reduction of induced hypoglycaemic risk represents the secondary objective beside the main goal of avoiding hyperglycaemia. Fast-acting analogues, by a faster dissociation of their hexameric conformation after their injection or infusion in subcutaneous tissue, reduce post-meal hyperglycaemia, while their shortened duration of action versus regular insulin minimizes late post-absorptive risk of hypoglycaemia. Long-acting analogues, by their precipitation in subcutaneous tissue or their slowly reversible binding to albumin, provide a benefit on blood glucose stability versus NPH or zinc insulins. Continuous insulin therapy using pumps offers both a better blood glucose stability than multiple daily injections and a broader flexibility in life mode. Using the peritoneal route by implantable pumps is a mean to improve blood glucose stability in poorly controlled patients in spite of optimized subcutaneous insulin therapy. The development of glucose sensors provides reinforced information on blood glucose, versus self-monitoring by capillary blood measurements, that contributes to a better adaptation of insulin therapy. First trials of connections between blood glucose data and insulin delivery open a perspective toward glucose-modulated insulin therapy, at least in periods outside meals, leading to first models of semi-automated artificial endocrine pancreas. The alternative of a cellular insulin supply by pancreas or islet transplantation looked promising during recent years, but lack of transplants and adverse events related to immune suppression limit their use to very specific cases where benefit/risk ratio is positive.     

Superiority of insulin analogues versus human insulin in the treatment of diabetes mellitus

The modern goals of insulin replacement in Type 1 and Type 2 diabetes mellitus (T1, T2DM) are A1C <6.5% long-term, and prevention of hypoglycaemia (blood glucose, BG <70 mg/dl). In addition to appropriate education and motivation of diabetic subjects, the use of rapid- and long-acting insulin analogues, is critical to achieve these goals. The benefits of rapid-acting analogues (lispro, aspart and glulisine have similar pharmacodynamic effects) compared with non-modified human regular insulin, are: (a) lower 1- and 2-h post-prandial blood glucose; (b) lower risk of late post-prandial hypoglycaemia (and therefore lower BG variability); (c) better quality of life (greater flexibility in timing and dosing of insulin). In T1DM, rapid-acting analogues improve A1C only by the extent to which replacement of basal insulin is optimized at the same time, either by multiple daily NPH administrations, or continuous subcutaneous insulin infusion (CSII), or use of the long-acting insulin analogues glargine or detemir. In T2DM, rapid-acting analogues reduce post-prandial hyperglycaemia more than human regular insulin, but systematic studies are needed to examine the effects on A1C. The benefits of long-acting insulin analogues glargine and detemir vs. NPH, are: (1) lower fasting BG combined with lower risk of hypoglycaemia in the interprandial state (night); (2) lower variability of BG. Glargine and detemir differ in terms of potency and duration of action. Detemir should be given twice daily in the large majority of people with T1DM, and in a large percentage of subjects with T2DM as well, usually at doses greater vs those of the once daily glargine. However, when used appropriately for individual pharmacokinetics and pharmacodynamics, glargine and detemir result into similar effects on BG, risk of hypoglycaemia and A1C. Rapid- and long-acting insulin analogues should always be combined in the treatment of T1 and T2DM.     

Central action of insulin regulates pulsatile luteinizing hormone secretion in the diabetic sheep model

This study tested the hypothesis that central mechanisms regulating luteinizing hormone (LH) secretion are responsive to insulin. Our approach was to infuse insulin into the lateral ventricle of six streptozotocin-induced diabetic sheep in an amount that is normally present in the CSF when LH secretion is maintained by peripheral insulin administration. In the first experiment, we monitored cerebrospinal fluid (CSF) insulin concentrations every 3-5 h in four diabetic sheep given insulin by peripheral injection (30 IU). The insulin concentration in the CSF was increased after insulin injection, and there was a positive relationship between CSF and plasma concentrations of insulin (r = 0.80, P < 0.01). In the second experiment, peripheral insulin administration was discontinued, and the sheep received either an intracerebroventricular (i.c.v.) infusion of insulin (12 mU/day in 2.4 ml saline) or saline (2.4 ml/day) for 5 days (n = 6) in a crossover design. The dose of insulin (i.c.v.) was calculated to approximate the increase in CSF insulin concentration found after peripheral insulin treatment. To monitor LH secretory patterns, blood samples were collected by jugular venipuncture at 10-min intervals for 4 h on the day before and 5 days after the start of i.c.v. insulin infusion. To monitor the increase in CSF insulin concentrations, a single CSF sample was collected one and four days after the start of the central infusion. The i.c.v. insulin infusion increased CSF insulin concentrations above those in saline-treated animals (P < 0.05) and maintained them at or above the peak levels achieved after peripheral insulin treatment. Central insulin infusion did not affect peripheral (plasma) insulin or glucose concentrations. LH pulse frequency in insulin-treated animals was greater than that in saline-treated animals (3.5 +/- 0.2 vs. 2.3 +/- 0.3 pulses/4 h, P < 0.01), but it was less than that during peripheral insulin treatment (4.8 +/- 0.2 pulses/4 h, P < 0.01). Our findings suggest that physiologic levels of central insulin supplementation are able to increase pulsatile LH secretion in diabetic sheep with low peripheral insulin. These results are consistent with the notion that central insulin plays a role in regulating pulsatile GnRH secretion.