Effect of hyperthyroidism on clearance and secretion of glucagon in man.

OBJECTIVE: Glucagon has been proposed to contribute to the increased glucose production found in hyperthyroidism. However, fasting plasma glucagon levels are not increased in hyperthyroidism suggesting that the activity of the α-cell is normal. Nevertheless, an increase in the clearance rate of glucagon may mask increased glucagon secretion. This study was designed to examine the effects of hyperthyroidism on the kinetics of glucagon. DESIGN AND METHODS: A primed-continuous infusion of glucagon was administered to 9 euthyroid and 9 hyperthyroid subjects at 3 sequential rates (1,200, 3,000 and 6,000 pg/kg/min, each given for 2 h). Arterialized blood was drawn at 15-30 min intervals for determination of glucagon. RESULTS: Fasting plasma glucagon levels were comparable in euthyroids (195±8 pg/ml) and hyperthyroids (231±16 pg/ml). During infusions (1,200, 3,000 and 6,000 pg/kg/min), plasma glucagon increased to 387±19, 624±44 and 977±51 pg/ml in euthyroids and to 348±23, 597±42 and 938±56 pg/ml in hyperthyroids respectively. At these infusion rates, metabolic clearance of glucagon (ml/kg/min) was 6.6±0.5, 7.4±0.6 and 7.9±0.5 in euthyroids and 12.6±2, 8.9±1 and 8.8±0.6 in hyperthyroids, respectively. Metabolic clearance of glucagon differed between hyperthyroids and euthyroids at 1 200 pg/kg/min infusion rate (p=0.001). The basal delivery rate of glucagon (ng/kg/min) was 1.3±0.1 in euthyroids and 2.9±0.6 in hyperthyroids (p=0.0005). CONCLUSIONS: In hyperthyroidism, the secretion and metabolic clearance rates of glucagon are increased. These effects may explain the changes in plasma glucagon levels observed in hyperthyroidism and support the important role of glucagon in increasing endogenous glucose production in this condition.

Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications.

Considerable data have accumulated over the past 20 years, indicating that the human kidney is involved in the regulation of glucose via gluconeogenesis, taking up glucose from the circulation, and by reabsorbing glucose from the glomerular filtrate. In light of the development of glucose-lowering drugs involving inhibition of renal glucose reabsorption, this review summarizes these data. Medline was searched from 1989 to present using the terms 'renal gluconeogenesis', 'renal glucose utilization', 'diabetes mellitus' and 'glucose transporters'. The human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the post-absorptive state. In the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis increases by approximately twofold. Glucose utilization by the kidneys after an overnight fast accounts for approximately 10% of glucose utilized by the body. Following a meal, glucose utilization by the kidney increases. Normally each day, approximately 180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and, when plasma glucose concentrations exceed a threshold, glucose appears in the urine. Handling of glucose by the kidney is altered in Type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the post-absorptive and postprandial states, and renal glucose reabsorption is increased. Specific SGLT2 inhibitors are being developed as a novel means of controlling hyperglycaemia in T2DM.

Nateglinide, alone or in combination with metformin, is effective and well tolerated in treatment-naïve elderly patients with type 2 diabetes.

AIM: The aim of this work was to assess the efficacy and tolerability of nateglinide alone or in combination with metformin in elderly patients with type 2 diabetes (T2DM). METHODS: Study 1 was a 12-week, multicentre, randomized, double blind and placebo-controlled study of nateglinide monotherapy (120 mg, before meals) in 66 drug-naïve patients with T2DM aged >or=65 years. Study 2 was a 104-week, multicentre, randomized, double blind and active-controlled study of nateglinide (120 mg, before meals) or glyburide (up to 5 mg bid) in combination with metformin (up to 1000 mg bid) in 69 treatment-naïve patients with T2DM aged >or=65 years. HbA(1c), fasting and postprandial glucose levels, and safety assessments were made. RESULTS: In Study 1, nateglinide significantly reduced HbA(1c) from baseline (7.6 +/- 0.1% to 6.9 +/- 0.1%; Delta = -0.7 +/- 0.1%, p < 0.001) and compared with placebo (between-group difference = -0.5%, p = 0.004 vs. nateglinide). No hypoglycaemia was reported. In Study 2, combination therapy with nateglinide/metformin significantly reduced HbA(1c) from baseline (7.8 +/- 0.2% to 6.6 +/- 0.1%; Delta = -1.2 +/- 0.2%, p < 0.001), as did glyburide/metformin (7.7 +/- 0.1% to 6.5 +/- 0.1%; Delta = -1.2 +/- 0.1%, p < 0.001). There was no difference between treatments (p = 0.310). One nateglinide/metformin-treated patient experienced a mild hypoglycaemic episode compared with eight episodes in eight patients on glyburide/metformin; one severe episode led to discontinuation. Target HbA(1c) (<7.0%) was achieved by 60% of patients receiving nateglinide (Study 1) and 70% of nateglinide/metformin-treated patients (Study 2). CONCLUSION: Initial drug treatment with nateglinide, alone or in combination with metformin, is well tolerated and produces clinically meaningful improvements in glycaemic control in elderly patients with T2DM.

Effects of pioglitazone on fasting and postprandial levels of lipid and hemostatic variables in overweight non-diabetic patients with coronary artery disease.

OBJECTIVES: To evaluate the effects of pioglitazone on insulin sensitivity and levels of biomarkers associated with thrombotic risk in overweight and obese, non-diabetic subjects with coronary artery disease. BACKGROUND: Little information is available regarding the effects of thiazolidinediones in the absence of diabetes. Further, although postprandial hyperlipemia is a risk factor for cardiovascular diseases, there is limited information about the postprandial effects. METHODS: Twenty overweight and obese, non-diabetic patients with coronary artery disease were enrolled in a randomized, placebo-controlled, double-blind study. Subjects were on atorvastatin for the duration of the study and received either placebo or pioglitazone (45 mg day(-1)) for 12 weeks and then crossed over to the alternative therapy for an additional 12 weeks. Insulin sensitivity, fasting and postprandial levels of lipid, hemostatic, and inflammatory variables were measured, and endothelial function was assessed. RESULTS: Insulin sensitivity improved from 0.03 micromol kg(-1) x min pM(-1) on placebo to 0.04 on pioglitazone (P = 0.0002), and there were decreases in fasting levels of factor (F) VII:C (102 +/- 17% to 92 +/- 18%, P = 0.001), FVII:Ag (68 +/- 12% to 60 +/- 14%, P = 0.01) and in von Willebrand factor (VWF) (174 +/- 94% to 142 +/- 69%, P = 0.01). Pioglitazone lowered postprandial levels of FVII:Ag, FVII:C, plasminogen activator inhibitor-1, VWF, and triglycerides, and increased high-density lipoproteins (+9%, P = 0.02). CONCLUSIONS: Pioglitazone improves insulin sensitivity and favorably modifies fasting and postprandial lipid, hemostatic and inflammatory markers of the metabolic syndrome in overweight and obese non-diabetic patients with coronary artery disease.

Hypoglycemic potential of nateglinide versus glyburide in patients with type 2 diabetes mellitus.

Antidiabetic agents that augment insulin secretion can cause hypoglycemia. With the current trend toward early and aggressive treatment of patients with type 2 diabetes, the hypoglycemic potential of insulinotropic agents is of concern. This study aimed to compare the propensity of the "glinide," nateglinide, and the sulfonylurea (SU), glyburide, to elicit hypoglycemia in type 2 diabetic patients with moderately elevated fasting plasma glucose (FPG). Hyperglycemic clamps (target plasma glucose = 11.1 mmol/L) were initiated, and 30 minutes later patients received a single oral dose of nateglinide (120 mg, n = 15) or glyburide (10 mg, n = 12) in a double-blind fashion. At the end of the 2-hour clamp when the glucose infusion was terminated, plasma glucose and insulin levels were measured for 4 additional hours. The minimum plasma glucose level achieved after terminating the glucose infusion (glucose nadir) was used as an index of hypoglycemic potential. The mean (+/-SEM) glucose nadir was significantly lower in patients given glyburide (3.3 +/- 0.2 mmol/L) versus nateglinide (4.4 +/- 0.3 mmol/L, P = .025). Confirmed hypoglycemia (plasma glucose < or = 2.8 mmol/L) occurred in 2 of 12 patients given glyburide and in none of those given nateglinide. Plasma insulin levels were significantly higher from 100 to 240 minutes after clamp termination in patients given glyburide versus nateglinide. Nateglinide has less hypoglycemic potential than glyburide, suggesting that nateglinide may be a more appropriate insulinotropic agent for patients with moderate fasting hyperglycemia, such as elderly patients and those with comorbid cardiac ischemia.

Insulin secretion, insulin sensitivity, and hepatic insulin extraction in first-degree relatives of type 2 diabetic patients.

To identify early metabolic abnormalities in type 2 diabetes mellitus, we measured insulin secretion, sensitivity to insulin, and hepatic insulin extraction in 48 healthy normal glucose-tolerant Brazilians, first-degree relatives of type 2 diabetic patients (FH+). Each individual was matched for sex, age, weight, and body fat distribution with a person without history of type 2 diabetes (FH-). Both groups were submitted to a hyperglycemic clamp procedure (180 mg/dl). Insulin release was evaluated in its two phases. The first was calculated as the sum of plasma insulin at 2.5, 5.0, 7.5, and 10.0 min after the beginning of glucose infusion, and the second as the mean plasma insulin level in the third hour of the clamp procedure. Insulin sensitivity index (ISI) was the mean glucose infusion rate in the third hour of the clamp experiment divided by the mean plasma insulin concentration during the same period of time. Hepatic insulin extraction was determined under fasting conditions and in the third hour of the clamp procedure as the ratio between C-peptide and plasma insulin levels. FH+ individuals did not differ from FH- individuals in terms of the following parameters [median (range)]: a) first-phase insulin secretion, 174 (116-221) vs 207 (108-277) microU/ml, b) second-phase insulin secretion, 64 (41-86) vs 53 (37-83) microU/ml, and c) ISI, 14.8 (9.0-20.8) vs 16.8 (9.0-27.0) mg kg-1 min-1/ microU ml-1. Hepatic insulin extraction in FH+ subjects was similar to that of FH- ones at basal conditions (median, 0.27 vs 0.27 ng/microU) and during glucose infusion (0.15 vs 0.15 ng/ micro U). Normal glucose-tolerant Brazilian FH+ individuals well-matched with FH- ones did not show defects of insulin secretion, insulin sensitivity, or hepatic insulin extraction as tested by hyperglycemic clamp procedures.

Insulin secretion, insulin sensitivity, and hepatic insulin extraction in first-degree relatives of type 2 diabetic patients

To identify early metabolic abnormalities in type 2 diabetes mellitus, we measured insulin secretion, sensitivity to insulin, and hepatic insulin extraction in 48 healthy normal glucose-tolerant Brazilians, first-degree relatives of type 2 diabetic patients (FH+). Each individual was matched for sex, age, weight, and body fat distribution with a person without history of type 2 diabetes (FH-). Both groups were submitted to a hyperglycemic clamp procedure (180 mg/dl). Insulin release was evaluated in its two phases. The first was calculated as the sum of plasma insulin at 2.5, 5.0, 7.5, and 10.0 min after the beginning of glucose infusion, and the second as the mean plasma insulin level in the third hour of the clamp procedure. Insulin sensitivity index (ISI) was the mean glucose infusion rate in the third hour of the clamp experiment divided by the mean plasma insulin concentration during the same period of time. Hepatic insulin extraction was determined under fasting conditions and in the third hour of the clamp procedure as the ratio between C-peptide and plasma insulin levels. FH+ individuals did not differ from FH- individuals in terms of the following parameters [median (range)]: a) first-phase insulin secretion, 174 (116-221) vs 207 (108-277) æU/ml, b) second-phase insulin secretion, 64 (41-86) vs 53 (37-83) æU/ml, and c) ISI, 14.8 (9.0-20.8) vs 16.8 (9.0-27.0) mg kg-1 min-1/æU ml-1. Hepatic insulin extraction in FH+ subjects was similar to that of FH- ones at basal conditions (median, 0.27 vs 0.27 ng/æU) and during glucose infusion (0.15 vs 0.15 ng/æU). Normal glucose-tolerant Brazilian FH+ individuals well-matched with FH- ones did not show defects of insulin secretion, insulin sensitivity, or hepatic insulin extraction as tested by hyperglycemic clamp procedures

Redefining the clinical management of type 2 diabetes: matching therapy to pathophysiology.

Conventional treatments for type 2 diabetes do not provide adequate glycaemic control to prevent the long-term progression of the disease. The introduction of increasingly intensive therapeutic regimens in stepwise management strategies aims to maintain glycaemic control in the face of progressive deterioration in beta-cell function. However, such an approach does not entirely address the underlying disease mechanisms. Although much remains unclear about the aetiology of type 2 diabetes, both beta-cell dysfunction and insulin resistance play important roles, and there is a complex, dynamic interaction between these two abnormalities. Growing evidence suggests that treatments that can reverse insulin resistance and improve beta-cell function may be able to slow or prevent the progression of the disease. The clinical management of type 2 diabetes therefore needs to be re-examined and redefined to reflect new insights into the underlying pathogenetic mechanisms, including consideration of the potential benefits of early, aggressive intervention to counter both beta-cell dysfunction and insulin resistance.

Brazilian individuals with impaired glucose tolerance are characterized by impaired insulin secretion.

BACKGROUND: To better understand the pathogenesis of type 2 diabetes mellitus, insulin secretion and insulin sensitivity (IS) were evaluated in white Brazilians with impaired glucose tolerance (IGT), using the oral glucose tolerance test (OGTT) and the hyperglycemic clamp technique. METHODS: Twenty-five IGT subjects were individually matched with normal glucose-tolerant (NGT) subjects for demographic characteristics. At first, they were submitted to the OGTT and plasma glucose and insulin were measured. Of the 25 pairs, 20 could participate in the hyperglycemic clamp procedures, at a second visit. All participants had their plasma glucose levels equally increased to 180 mg/dl; this was maintained for three hours by variable glucose infusion. During the procedure, plasma glucose and insulin were measured at established intervals. RESULTS: In the postabsorptive state, the IGT subjects presented higher levels of plasma glucose, blood HbA1, and serum triglycerides, but similar plasma insulin levels. After the oral glucose load, early and total insulin release, in relation to glucose levels, were respectively, 43 and 67% lower in the IGT individuals. The index of whole-body IS was increased in the IGT individuals (4.36 +/- 1.71 vs 3.61 +/- 1.28 mg(-1). micro U(-1).100.ml2; p<0.05). By the hyperglycemic clamp technique first- (82 +/- 26 vs 215 +/- 88 micro U/ml; p<0.001) and second- (36 +/- 19 vs 73 +/- 44 micro U/ml; p<0.05) phases of insulin secretion was decreased in the IGT individuals, especially the first one. However, the groups did not differ in relation to the IS: IGT=13.52 +/- 7.27 and NGT=9.96 +/- 6.70 mg.ml/kg. micro U.min(-1); p > 0.05. Functional relationship of IS (y) on first-phase insulin release (x) showed a smaller (p<0.05) regression coefficient for the IGT group. CONCLUSION: Brazilians with IGT well-matched with NGT ones were characterized by impaired first- and second-phase insulin secretion (mainly the former), while defects in IS were not evident.

Matching treatment to pathophysiology in type 2 diabetes.

BACKGROUND: Because type 2 diabetes is a progressive condition, >50% of all patients whose disease is initially controlled with diet and exercise will eventually need single or multiple pharmacologic agents to maintain adequate glycemic control. Although current treatment standards require that combination therapy be instituted only after the failure of monotherapy, the results of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study suggest that aggressive initial treatment is crucial to slowing the evolution of long-term complications associated with this disease. OBJECTIVES: This article reviews the diagnosis and classification of type 2 diabetes, describes the multiple defects in glucose metabolism associated with the disease, and discusses the various pharmacologic options for achieving glycemic control in these patients. METHODS: The information in this review was compiled through a search of MEDLINE. Search terms included but were not limited to type 2 diabetes and antihyperglycemic agents. In addition, abstracts were identified using the Web sites of diabetes-related professional organizations. RESULTS: Two pathophysiologic mechanisms, insulin resistance and impaired insulin secretion, are usually present at diagnosis in type 2 diabetes. Several studies have shown that combination therapy with antihyperglycemic agents having different mechanisms of action provides greater efficacy than treatment with single agents. CONCLUSIONS: Current research suggests that early aggressive treatment with combination therapy achieves glycemic control at lower doses and with fewer side effects than monotherapy with either component.

Renal gluconeogenesis: its importance in human glucose homeostasis.

Studies conducted over the last 60 years in animals and in vitro have provided considerable evidence that the mammalian kidney can make glucose and release it under various conditions. Until quite recently however, it was generally believed that the human kidney was not an important source of glucose except during acidosis and after prolonged fasting. This review will summarize early work in animals and humans, discuss methodological problems in assessing renal glucose release in vivo, and present results of recent human studies that provide evidence that the kidney may play a significant role in carbohydrate metabolism under both physiological and pathological conditions.

Relative conributions of beta-cell function and tissue insulin sensitivity to fasting and postglucose-load glycemia.

We performed hyperglycemic clamps in 283 nondiabetic Caucasians and, with multiple linear regression, determined the contribution of beta-cell function and tissue insulin sensitivity to variations in glycemia and insulinemia during oral glucose tolerance tests (OGTTs). Impaired glucose tolerance (IGT) subjects had reduced insulin sensitivity (P < .02) and beta-cell function (P < .0001). Normal glucose tolerance (NGT) subjects with first-degree type 2 diabetic relatives had reduced first and second phase insulin secretion (both, P < .05), but normal insulin sensitivity (P = .37). Beta-Cell function and insulin sensitivity accounted for one fourth of the variability in glucose tolerance. Fasting plasma glucose in subjects with NGT (n = 185) was a function of both phases of insulin secretion and of insulin sensitivity (all, P < .05), whereas, in IGT subjects (n = 98), it was a function of first phase insulin secretion and insulin sensitivity (P < .01). Two-hour glycemia was a function of second phase secretion and insulin sensitivity (P < .01). Fasting and 2-hour plasma insulin levels were determined by insulin sensitivity (and glycemia) in NGT subjects (P < .001), but by second phase secretion in IGT (P < .001). We conclude that beta-cell function is reduced in subjects with IGT; glycemia and insulinemia are not regulated by the same mechanisms in IGT and NGT; insulin sensitivity does not contribute to insulinemia in IGT; family history of diabetes influences beta-cell function, but not insulin sensitivity in Caucasians.

Addressing the insulin secretion defect: a logical first-line approach.

The pathogenesis of type 2 diabetes has been an area of intense investigation, considerable controversy, and continuing discovery. It is now clear that this is a heterogeneous condition both phenotypically and genotypically, and that acquired reversible abnormalities/risk factors also play an important role. Currently, type 2 diabetes can be viewed as developing in genetically susceptible individuals, who, because of impaired beta-cell function, are incapable of increasing their insulin release appropriately to compensate for reduced insulin sensitivity which is acquired through life for various reasons (eg, obesity, aging, physical inactivity, drug use, or diet). As our knowledge of the interplay of these elements increases, there will be important consequences regarding the choice of the most appropriate therapeutic approach for individual patients. This review will analyze issues pertaining to the interaction of reduced insulin sensitivity and impaired beta-cell function in type 2 diabetes, specifically: which is the primary genetic factor, which is more important in determining hyperglycemia, what is the most important site affected by impaired beta-cell function and insulin sensitivity, and which, if any, should be the preferential target for therapeutic intervention.

Hormonal control of renal and systemic glutamine metabolism.

Glutamine is the most abundant free amino acid in the human body. Recent studies indicate that it may be an important vehicle for interorgan nitrogen and carbon transport. However, relatively little is known about hormonal factors regulating its metabolism in humans. We review here our recent work on the effects of insulin, glucagon and epinephrine on plasma glutamine kinetics and its conversion to glucose by liver and kidney.

Reversal of hypoglycemia unawareness in a long-term type 1 diabetic patient by improvement of beta-adrenergic sensitivity after prevention of hypoglycemia.

The purpose of this study was to assess the effect of strict avoidance of hypoglycemia on beta-adrenergic sensitivity in a type 1 diabetic patient with hypoglycemia unawareness and a diabetes duration of 55 yr. beta-Adrenergic sensitivity was determined by an isoproterenol test and was expressed as the lowest dose of isoproterenol that increases the heart rate by 25 beats/min (IC25). Plasma epinephrine and symptom responses to hypoglycemia were determined during a 3-h hypoglycemic (3 mmol/L) clamp. Initially, the patient had a near-normal counterregulatory plasma epinephrine response to hypoglycemia but reduced beta-adrenergic sensitivity (IC25, 2 microg) compared to 10 hypoglycemia aware, type 1 diabetic patients (0.65 +/- 0.14 microg) and 10 normal control subjects (1.13 +/- 0.21 microg). After 1 yr of strict avoidance of blood glucose levels below 4 mmol/L, the IC25 decreased to 0.25 microg, reflecting improved beta-adrenergic sensitivity. In conclusion, the reduced beta-adrenergic sensitivity in this patient was probably the reason for hypoglycemia unawareness and was reversed by strict avoidance of hypoglycemia.