Endogenous Insulin Secretory Capacity Research Articles

NIDDMにおける脂質代謝の検討

Recently, it has been shown that hyperinsulinemia is an independent risk factor of atherosclerosis and that non-insulin-dependent diabetic (NIDD) patients undergo transition to hyperinsulinemia due to their insulin resistance or exogenously injected insulin. Therefore, it is important to study the role of hyperinsulinemia in atherogenesis of NIDD patients in relation to their lipid metabolism to obtain a better understanding of the prognosis of these patients. Total cholesterol (TC), triglyceride, HDL-cholesterol (HDL-C) and apoproteins (Apo A-I, A-II, B, C-II, C-III, E) were examined as the parameters of lipid metabolism and the endogenous insulin secretory capacity was assessed by the c-peptide level 5 minutes after glucagon injection (5-CPR). Lipid studies were performed on 38 controls and 67 NIDD patients and glucagon test on 10 controls and 67 NIDD patients. Patients were divided into two groups based on the 5-CPR results. The low responder (LR) group consisted of 5-CPR<1.8ng/ml and the responder (R) group≥1.8ng/ml. HDL-C, Apo A-I and TC/Apo B were lower in the R group than the LR group. In contrast, Apo B, Apo E and B/A-I were higher in the R group than the LR group. These results suggest that lipid metabolism of NIDD patients with a residual endogenous insulin secretory capacity was more atherogenic than that in patients with a low endogenous insulin secretory capacity.

Interaction of bromocriptine and cyclosporine in insulin dependent diabetes mellitus: Results from the Canadian open study

Although cyclosporine A (Cy-A) is effective in modifying the initial course of newly diagnosed insulin dependent diabetes mellitus (IDDM) it has a number of side effects, particularly renal, which limit its use. In this study we investigated the potential synergistic effects of bromocriptine (BCR) therapy in treating patients with newly diagnosed IDDM. Three groups of patients were treated: (1) fourteen patients on Cy-A who required a decrease in their dose due to elevated creatinine; (2) four newly diagnosed patients whose initial therapy consisted of low dose (5 mg/kg/day) Cy-A and 10 mg/day of BCR; (3) eight patients whose glucagon-stimulated connecting-peptide (C-peptide) levels were greater than 0.3 nmol/l but whose insulin requirements were over 0.3 U/kg/day and whose Cy-A was to be discontinued. The results suggest that there was no statistically significant difference in stimulated C-peptide, glycosylated haemoglobin, daily insulin dose or serum creatinine. However, the trend suggested that BCR may have some protective effect on preserving endogenous insulin secretory capacity, although glycosylated haemoglobin and daily insulin dose increased. The results do not suggest that patients with newly diagnosed IDDM significantly benefit from concurrent BCR and Cy-A therapy.

Effects of glyburide on In Vivo insulin-mediated glucose disposal

The purpose of this study was to examine the effects of glyburide on peripheral (muscle) and hepatic insulin sensitivity in patients with non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) as well as in healthy control subjects. In protocol 1, 10 patients with NIDDM and seven young healthy control subjects were studied. Changes in insulin sensitivity (40 frsol| mU/ m 2 · min euglycemic insulin clamp), hepatic glucose production (3-[ 3H]glucose turnover), and insulin secretion (+125 mg/dL) hyperglycemic clamp) were measured before and after 3 months (in patients with NIDDM) and 6 weeks (in young control subjects) of glyburide therapy. In protocol 2, five patients with IDDM and eight patients with insulin-treated NIDDM were evaluted before and after two months of glyburide therapy (20 mg per day). Changes in daily insulin requirements, 24-hour plasma glucose profiles, glycohemoglobin, glucagon-stimulated C-peptide secretion, insulin sensitivity, and hepatic glucose production were measured. In protocol 1, glyburide significantly improved insulin sensitivity (p <0.01) and insulin secretion (p <0.01) in the NIDDM patients. The elevated rates of hepatic glucose production (2.4 ± 0.3 mg/kg · min) were reduced after glyburide therapy (1.7 ± 0.2 mg/kg · min; p <0.01) and were highly correlated with an improvement in fasted plasma glucose levels (r = 0.92; p <0.001). Insulin sensitivity also improved in the young healthy control subjects after glyburide therapy (6.5 ± 0.5 to 7.6 ± 0.7 mg/kg · min; p <0.05). In protocol 2, glyburide treatment produced no changed in daily insulin requirement (54 ± 8 versus 53 ± 7 units per day), mean 24-hour glucose levels (177 ± 20 versus 174 ± 29 mg/dL), glycohemoglobin (10.1 ± 1.0 percent versus 9.5 ± 7 percent), C-peptide secretion, insulin sensitivity, or basal hepatic glucose production (p values not significant) in the IDDM patients. In contrast, the insulin-treated NIDDM patients had siginificant reductions in mean daily insulin requirement (72 ± 6 versus 58 ± 9 units per day; p = 0.05), mean 24-hour plasma glucose levels (153 ± 10 to 131 ± 5 mg/dL; p <0.05), and glycohemoglobin levels (10.3 ± 0.7 percent to 8.0 ± 0.4 percent; p 0.05) and an improvement in C-peptide secretion (0.24 ± 0.07 to 0.44 ± 0.09 pmol/mL; p = 0.08). Stimulated C-peptide levels were highly correlated with a reduction in insulin dose observed during the 2-month treatment period (r = 0.93; p <0.001). Insulin sensitivity improved slightly but not significantly after glyburide treatment. It is concluded that glyburide improves glycemic control by a combination of mechanisms, including: (1) enhancement of peripheral (muscle) insulin sensitivity; (2) reduction in basal hepatic glucose production; and (3) potentiation of glucose-stimulated insulin secretion. Because no benefit is observed in IDDM patients, it appears that shome endogenous insulin secretory capacity is required for these effects to become evident.

Association of serum lipids and lipoproteins with plasma C-peptide concentration in non-insulin-dependent diabetic and non-diabetic subjects

Serum lipids and lipoproteins were studied in 149 non-insulin-dependent diabetic subjects treated with diet or oral drugs (75 men, 74 women) and in 101 nondiabetic control subjects (49 men, 52 women) in relation to endogenous insulin secretion capacity measured by plasma C-peptide response to intravenous glucagon. Serum HDL- and HDL 2-cholesterol concentrations were lower and VLDL-cholesterol and total and VLDL-triglyceride concentrations higher in subjects with high C-peptide response (above the median) than in subjects with low C-peptide response (lower or equal to median) both in diabetic and control subjects of both sexes. Adjustment for the effect of obesity abolished these differences in serum lipids and lipoproteins in diabetic subjects but not in control subjects. This may indicate that obesity has stronger influence on serum lipids in diabetic subjects than in nondiabetic subjects.

Prevalence of insulin deficiency among initially non-insulin-dependent middle-aged diabetic individuals.

The endogenous insulin secretion capacity of 171 insulin-treated middle-aged persons with diabetes (81 men, 90 women) of the Kuopio University Central Hospital district (population 250,000), East Finland, was measured by the C-peptide response to glucagon. The prevalence of insulin deficiency among initially non-insulin-dependent diabetic (NIDDM) individuals was calculated on the basis of those who were initially treated with diet or oral drugs and 3 yr or more after diagnosis had been treated with insulin and were insulin deficient in this study. The prevalence of complete insulin deficiency (postglucagon C-peptide undetectable) was among initially NIDDM individuals of the same region, 0.7% in men and 1.2% in women. Using the postglucagon C-peptide level of 0.20 nmol/L as a cut-off point, the prevalence of insulin deficiency was 2.0% in men and 1.9% in women and, on the basis of C-peptide level of 0.60 nmol/L, the prevalence of insulin deficiency was 3.5% in men and 2.7% in women. Our data suggest that the deterioration of insulin secretion capacity in NIDDM to the level that leads to insulin dependency occurs less often than has been previously suggested.

Role of plasma C-peptide determination in the management of type II diabetes.

The classification of diabetes may be sometimes difficult, particularly in persons with non-ketotic diabetes becoming manifest in middle age. The plasma C-peptide concentration, determined either in the fasting state or, preferably, after stimulation with iv. glucagon, gives a reliable estimate of the endogenous insulin secretion capacity of the individual. The C-peptide determination has improved the facilities for classification of diabetes and for appropriate choice of therapy. Patients showing stimulated plasma C-peptide values less than 0.6 nmol/l are definitely insulin-dependent, whereas values above the limit indicate that the patients can probably be managed without exogenous insulin (non-insulin-dependent diabetes). The C-peptide determination alone does not definitely indicate the therapy of choice. Conventional indicators of energy balance and glucose control together with regular follow-up of patients are still essential, particularly in the management of patients showing relatively low plasma C-peptide levels (between 0.6 and 1.1 nmol/l.). The stimulated plasma C-peptide concentration should be determined always before stopping insulin therapy in any diabetic patient or before instituting insulin therapy in a nonketotic patient. In addition, plasma C-peptide determinations will certainly prove valuable in the classification of adult onset diabetic patients for the purposes of epidemiologic studies.

Biochemical characterization of ketosis-resistant young diabetics of northern India. In vivo effects of i.v. glucose, s.c. epinephrine and i.v. glucagon and in vitro effects of anti-insulin serum on adipose tissue lipolysis.

Epinephrine (10 micrograms/kg body weight) s.c., glucagon (1 microgram/kg body weight) i.v. and glucose (0.5 g/kg body weight) i.v. were injected in groups of ketosis-prone young diabetics, ketosis-resistant young diabetics, maturity-onset diabetics, young and mature controls, each group comprising 8 subjects. Samples were drawn at timed intervals and analyzed for glucose, FFA, acetone, citrate and plasma free insulin. FFA and glycerol release by the adipose tissue in vitro was studied in 6 of each of the following groups: young diabetics and young controls in the presence of norepinephrine, anti-insulin serum or both. Failure of the adipose tissue of ketosis-resistant young diabetics to respond to lipolytic and ketogenic hormones has been suggested by others as the basis for the clinically observed resistance to ketoacidosis. The present data do not confirm any failure of the liver or adipose tissue to respond to glucagon, epinephrine or norepinephrine in these diabetics. The ketosis-resistant young diabetics have some endogenous insulin secretory capacity still preserved as evident from their basal and post-glucose free insulin levels and effects of anti-insulin serum on in vitro lipolysis by their adipose tissues. The available endogenous insulin though adequate in preventing excessive lipolysis and ketogenesis, appears insufficient to check hyperglycemia.

The storage and synthetic pools of heparin-releasable lipoprotein lipase and hepatic triacylglycerol lipase in the growing puppy.

Age-related changes in the activities of extrahepatic lipoprotein lipase and hepatic triacylglycerol lipase were determined during a primed/constant-rate infusion of heparin for 2 h in puppies between birth and 18 weeks of age. The early (storage) and late (synthetic) phases were measured. Both phases of hepatic triacylglycerol lipase activity were well developed in the first week, reflecting the metabolic maturity of the liver at birth. During the 18 weeks of study, the activity remained relatively unchanged except for a sharp peak at 12 weeks. Extrahepatic lipoprotein lipase activity was low in the first 4 weeks of suckling. Its storage pool increased 6-fold in the next 14 weeks, with a less marked rise in its late (synthetic) pool. Sustained increases in the activity of this enzyme were first noticed during weaning, when the insulin-secretory response matured. Endogenous insulin-secretory capacity rather than the fat content of the feed appeared significant in the postnatal development of lipoprotein lipase (Clearing-factor lipase) activity.

Does pregnancy influence the prognosis of uncomplicated insulin-dependent diabetes mellitus?

To evaluate the effect of one or two pregnancies on the prevalence and severity of late diabetic complications, 22 pairs (44 patients) of female insulin-dependent diabetic (IDDM) patients were examined. Each pair consisted of one patient who had completed one or two pregnancies and one who had not. The two groups were carefully matched with respect to age, duration of disease, endogenous insulin secretory capacity, quality of blood glucose control, insulin requirement, hospitalization, and social status. No differences in prevalence or severity of retinopathy, nephropathy, and neuropathy were found.

Sulphonylureas increase the number of insulin receptors.

SULPHONYLUREA drugs have been widely used in the management of the form of diabetes mellitus which develops in adulthood. Although some endogenous insulin secretory capacity seems to be necessary for Sulphonylureas to be effective (they are ineffective in pancreatectomised animals), their precise mechanism of action has not been clear. Short-term administration of Sulphonylureas to animals or humans is associated with increased insulin secretion1,2. However, prolonged administration reduces pancreatic insulin content in animals3,4 and diminished insulin secretion in reponse to nutrient stimulation in both laboratory animals5 and humans with adult-onset (insulin-independent) diabetes6,7. Treatment with sulphonylureas also decreases the biosynthesis of proinsulin8. Thus, the chronic antidiabetic action of Sulphonylureas does not seem to result from an effect on insulin release, but rather from one or more extrapancreatic effects9,10. In that connection, we have shown that chronic administration of the sulphonylurea, glipizide, to patients with adult-onset diabetes mellitus results in significant potentiation of insulin action, as assessed by changes in insulin-mediated glucose disposal11. On the basis of those results, we have suggested that glipizide influences the interaction of insulin with the cell membranes in insulin-sensitive tissues. We now report that, in an animal model, such an effect involves an increase in the number of insulin receptors.

Studies with a pancreatic beta cell simulator in the third trimester of pregnancies complicated by diabetes

To determine the potential of an artificial pancreatic beta cell simulator★ as a therapeutic and research tool we have used the device for short-term monitoring and control of blood glucose concentrations in five pregnant patients with juvenile-onset diabetes (White's Class C) and three pregnant patients with maturity-onset diabetes (Class B). One patient with brittle juvenile-onset diabetes had successful control before, during, and after cesarean section. The other seven patients were studied during the third trimester of pregnancy and at least four weeks before delivery. Blood glucose control with Biostator regulation was excellent (mean, 96 mg. per deciliter; range, 85 to 107). The insulin requirements needed to achieve optimal glucose control with the Biostator were highly variable (range, 20 to 157 U. per 24 hours) but very similar to those previously calculated to provide optimal control by conventional means. Insulin requirements were unrelated to plasma growth hormone, placental lactogen, or glucagon concentrations. The greatest degree of insulin resistance was seen in obese patients with endogenous insulin-secretory capacity. This study indicates that a pancreatic beta cell simulator can normalize glucose concentrations and rapidly estimate daily insulin requirements in pregnant diabetic patients. In addition, the data suggest that exogenous insulin may indirectly suppress endogenous insulin secretion and thus contribute to the “insulin resistance” of obese patients with maturity-onset diabetes.

The contribution of endogenous insulin secretion to the ketogenic response to glucagon in man.

The magnitude and direction of the lipolytic and ketogenic responses following exogenous glucagon administration is controversial and consideration of the possible role of endogenous insulin secretion upon these events has not been clarified. The present study examines the role of endogenous insulin secretion in modulating the net lipolytic and ketogenic activity of glucagon. Three groups characterized by different levels of endogenous insulin secretory capacity were studied. In all three groups, the responses in plasma insulin, betahydroxybutyrate, and free fatty acids were observed following bolus administration of 1.0 mug/kg glucagon. In the obese subjects with increased endogenous insulin secretion, glucagon administration resulted in a decline below basal levels of both free fatty acid and betahydroxybutyrate. In the diabetic subjects with no demonstrable endogenous insulin secretion, glucagon administration was followed by a rise in plasma free fatty acids and an exaggerated rise in plasma betahydroxybutyrate. The normal control group exhibited a response in betahydroxybutyrate midway between the obese and diabetic groups. These obwervations support the thesis that the magnitude of endogenous insulin secretion modulates the lipolytic and ketogenic actions of glucagon in man.