Diversity of Insulin Resistance in Monkeys with Normal Glucose Tolerance

Insulin resistance has been proposed as a critical factor in the development of Type II diabetes, hypertension, dyslipidemia, and coronary artery disease. However, even in normal healthy individuals, a wide range of in vivo insulin action has been found. In the present study we sought to examine this heterogeneity in Insulin action in both normal and spontaneously obese nonhuman primates. Maximal insulin responsiveness as measured by a hyperinsulinemic euglycemic clamp, fasting plasma glucose, and insulin levels, β-cell insulin response to glucose, glucose tolerance, and adiposity were measured in 22 male rhesus monkeys. Results showed that lean animals (body fat ≤ 22%) had higher insulin-stimulated glucose uptake (M rate: 14.42±1.8 mg/kg FFM/min) compared to obese (8.08±0.8). The obese monkeys, with 23–49% body fat, had a wide range of M values (5.32-14.29 mg/kg FFM/min) which showed no relationship to degree of adiposity. In all monkeys, M values had a strong inverse correlation with fasting plasma insulin levels (r=-0.76; p<0.001), but not with fasting glucose or glucose disappearance rate. We conclude that neither degree of obesity above a critical threshold nor range of glucose tolerance is related to insulin resistance; however, in individuals with normal glucose tolerance an early reliable indicator of defective insulin action appears to be fasting insulin concentration. Longitudinal determination of basal insulin levels obtained under standardized conditions so as to minimize extraneous variability is likely to strengthen the ability to predict insulin resistance and possible later development of overt Type II diabetes.     

Ketosis-Prone Type 2 Diabetes: Effect of Hyperglycemia on β-Cell Function and Skeletal Muscle Insulin Signaling

ObjectiveTo determine the underlying mechanism for the severe and transient β-cell dysfunction and impaired insulin action in obese African American patients with ketosis-prone diabetes.MethodsThe effect of sustained hyperglycemia (glucotoxicity) and increased free fatty acids (lipotoxicity) on β-cell function was assessed by changes in insulin secretion during a 20-hour glucose (200 mg/m² per minute) and a 48-hour Intralipid (40 mL/h) infusion, respectively. Insulin-activated signaling pathways and pattern of Akt-1 and Akt-2 expression and insulin-stimulated phosphorylation were analyzed in skeletal muscle biopsy specimens. Studies were performed in an obese African American woman within 48 hours after resolution of diabetic ketoacidosis and 1 week after discontinuation of insulin treatment.ResultsDextrose infusion rapidly increased C-pep-tide levels from a baseline of 3.2 ng/mL to a mean of 7.1 ± 0.5 ng/mL during the first 8 hours of infusion; thereafter, C-peptide levels progressively declined. Lipid infusion was not associated with any deleterious effect on insulin and C-peptide secretion. Initial in vitro stimulation of muscle tissue with insulin resulted in a substantial and selectively decreased Akt-2 expression and insulin-stimulated phosphorylation on the serine residue. Improved metabolic control resulted in 70% greater Akt expression at near-normoglycemic remission in comparison with the period of hyperglycemia.ConclusionHyperglycemia, but not increased free fatty acid levels, led to progressive β-cell dysfunction and impaired insulin secretion. Hyperglycemia was also associated with diminished skeletal muscle Akt expression and phosphorylation in an African American woman with ketosis-prone diabetes, and this defect improved notably with aggressive insulin therapy. These results indicate the importance of glucose toxicity in the pathogenesis of keto-sis-prone diabetes in obese African American patients. (Endocr Pract. 2007;13:283-290)     

Development of hyperinsulinemia and insulin resistance during the early stage of weight gain

Obesity is associated with insulin resistance and hyperinsulinemia, which is considered to be a core component in the pathophysiology of obesity-related comorbidities. As yet it is unknown whether insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. In 10 healthy male subjects the effect of intentional weight gain by 2 BMI points was examined on insulin. C-peptide and glucose levels following a meal, 75 g of glucose, and a two-step hyperglycemic clamp increased plasma glucose by 1.38 and 2.75 mmol/l, respectively. Baseline insulin, C-peptide, and glucose concentrations were significantly higher after weight gain from 21.8 to 23.8 kg/m(2) BMI within 4(1/2) mo. Calculations of insulin secretion and clearance indicate that reduced insulin clearance contributes more to post-weight gain basal hyperinsulinemia than insulin secretion. Following oral or intravenous stimulation insulin concentrations were significantly higher post-weight gain during all three test conditions, whereas C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels, the rate of intravenous glucose required to maintain the defined elevation of glucose levels was either identical (1.38 mmol/l) or even significantly lower (2.75 mmol/l) following weight gain. The present study demonstrates for the first time that insulin resistance already develops during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively.     

Insulin and C-peptide secretion and kinetics in humans: direct and model-based measurements during OGTT

To directly evaluate prehepatic secretion of pancreatic hormones during a 3-h oral glucose tolerance test (OGTT), we measured insulin and C-peptide in six healthy control, six obese, and six type 2 diabetic subjects in the femoral artery and hepatic vein by means of the hepatic catheterization technique. Hypersecretion in obesity was confirmed (309 +/- 66 nmol in obese vs. 117 +/- 22 in control and 79 +/- 13 in diabetic subjects, P 0.3, r(2) = 0.93), whereas estimation of hepatic insulin extraction and insulin clearance needs further investigation for improvement.     

Insulin Levels,Physical Activity,and Urinary Catecholamine Excretion of Obese and Non-Obese Rhesus Monkeys

The hypothesis that spontaneous obesity in rhesus monkeys is associated with abnormalities in energy expenditure was tested. Obese (n=7) and non-obese (n=5) monkeys were described in terms of body size and composition, food intake, and physical activity. Additionally, the relationships among fasting and stimulated insulin levels in serum, C-peptide levels in serum and urine, and urinary catecholamines were examined. Obese animals had primarily abdominal deposition of excess body fat, as indicated by markedly elevated abdominal circumferences and skin-fold thicknesses. Food intake did not differ between groups. Physical activity was much lower in the obese group. Obese monkeys had markedly higher serum insulin and C-peptide levels in the fasted state and in response to an intravenous glucose challenge. Urinary excretion of C-peptide and catecholamines was measured during successive 2-day periods of ad libitum feeding, food deprivation, and refeeding in order to examine potential differences between groups in sympathoadrenal activity and their relationship to insulin secretion. C-peptide excretion was greater for obese and decreased for both groups during food deprivation. Urinary dopamine (DA), norepinephrine (NE), and epinephrine (E) levels were significantly greater for obese animals in all conditions. DA excretion was lowest during deprivation and E excretion was lowest during refeeding, whereas NE excretion was relatively unaffected by feeding condition. The overall patterns of C-peptide and catecholamine excretion were qualitatively similar for both groups, and there were no reliable differences between obese and non-obese in their responses to the feeding manipulation. The results suggest that hyperinsulinemia associated with obesity in rhesus monkeys is linked to increased catecholamine secretion and a resistance to cate-cholaminergic action.     

Basal and Stimulated Plasma Leptin in Diabetic Subjects

LIU, JIANMEI, HASAN ASKARI, AND SAMUEL DAGOGO-JACK. Basal and stimulated plasma leptin in diabetic subjects. Obes Res. Objective: To determine whether leptin secretion is impaired in diabetes, we compared basal and stimulated plasma leptin levels in diabetic subjects and healthy controls. Research Methods and Procedures: Blood samples for assay of leptin and other hormones were obtained at baseline in 54 diabetic patients and 65 controls, and 8 hours, 16 hours, and 40 hours following ingestion of dexamethasone (4 mg) in 6 healthy and 12 controls. C-peptide status was defined as “negative” if ≤0.1 ng/mL or “positive” if ≥0.3 ng/mL, in fasting plasma. Results: Basal plasma leptin levels were 19. 7±2. 2 ng/mL in nondiabetic subjects, 13. 4±1. 5 ng/ml in C-peptide negative (n = 28) and 26. 1±23. 7 ng/mL in C-peptide positive (n = 26, p = 0. 001) diabetic patients. Dexamethasone increased leptin levels of controls (n = 6) to 145±17% of baseline values at 8 hours (p = O. O3), 224±18% at 16 hours (p = 0. 01), and 134218% at 40 hours (p = 0. 05). The corresponding changes were 108±13%, 126±23%, and 98±16% in C-peptide negative (n = 6), and 121±10%, 144±16% (p = 0. 03), and 147±23% (p = 0. 11) in C-peptide positive (n = 6) diabetic patients, respectively. The peak stimulated leptin levels were lower in the diabetic patients, compared with controls. Plasma insulin increased (p = 0. 02) in controls, but not in the diabetic patients, following dexamethasone. Discussion: Although diabetic patients have normal plasma leptin levels under basal conditions, their leptin responses to glucocorticoid are impaired, probably because of the concomitant insulin secretory defect. A subnormal leptin secretory response could worsen obesity and insulin resistance in diabetes.     

Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice

The phosphatidylinositol-3-kinase-dependent kinase, Akt2, plays a central role in mediating insulin effects in glucose-metabolizing tissues. Akt2 knockout mice display insulin resistance with a reactive increase in pancreatic islet mass and hyperinsulinemia. The related phosphatidylinositol-3-kinase-dependent kinase, serum- and glucocorticoid-regulated kinase 3 (SGK3), is essential for normal postnatal hair follicle development but plays no apparent role in glucose homeostasis. We report here an unexpected role of SGK3 in islet β-cell function, which is revealed in Akt2/SGK3 double-knockout (DKO) mice. DKO mice have markedly worse glucose homeostasis than Akt2 single-null animals, including greater baseline glucose, and greater rise in blood glucose after glucose challenge. However, surprisingly, our data strongly support the idea that this exacerbation of the glucose-handling defect is due to impaired β-cell function, rather than increased insulin resistance in peripheral tissues. DKO mice had lower plasma insulin and C-peptide levels, lower β-cell mass, reduced glucose-stimulated insulin secretion, and greater sensitivity to exogenous insulin than Akt2 single nulls. We further demonstrated that SGK3 is strongly expressed in normal mouse islets and, interestingly, that β-catenin expression is dramatically lower in the islets of DKO mice than in those of Akt2(-/-)/SGK3(+/+) or Akt2(-/-)/SGK3(+/-) mice. Taken together, these data strongly suggest that SGK3 plays a previously unappreciated role in glucose homeostasis, likely through direct effects within β-cells, to stimulate proliferation and insulin release, at least in part by controlling the expression and activity of β-catenin.     

Impaired insulin secretion in the neonatal rhesus monkey after chronic hyperinsulinemia in utero

The secretion of insulin by the pancreas of the newborn rhesus monkey that had been made experimentally hyperinsulinemic in utero was studied in 18 animals. Chronic in utero hyperinsulinemia was produced by the continuous subcutaneous delivery of 4.75 units of insulin per day for 18 +/- 1 days. After delivery, the insulin-containing pump was removed to allow neonatal insulin levels to drop to normal levels. By 6.5 +/- 1.0 hr after pump removal, plasma glucose, insulin, and C-peptide immunoreactivity (CPIR) were comparable in the control and experimental animals. At that point 300 micrograms of glucagon/kg body weight was given iv to stimulate insulin secretion. After 30 min a significant elevation (expressed as the percentage of basal levels) in plasma glucose by 250%, insulin by 200%, and CPIR by 200% was observed in the control animals. In contrast, no changes in plasma insulin or CPIR concentrations occurred, with an attenuated glucose response that was only one-fifth of the control response, in the experimental animals. These results along with the observed lowered concentrations of CPIR in the plasma and insulin in the pancreas at birth can be interpreted as evidence that insulin is an inhibitor of its synthesis and secretion in utero and that this abnormal intrauterine environment causes changes that persist into extrauterine life.     

The pancreatic glucagon and C-peptide secretion during hyperinsulinemia in euglycemic glucose clamp with or without somatostatin infusion in normal man

6 normal subjects received two times of 2 hr euglycemic glucose clamp studies (insulin infusion rate 40 mU/M2/min) one with and the other without somatostatin (SRIF) infusion (500 microgram/hr). Serum C-peptide and glucagon levels were measured during clamp to study the sensitivity of pancreatic alpha and beta cells to the suppressive effects of exogenous hyperinsulinemia during normoglycemia in normal subjects and to find whether SRIF had any modulative effects on endocrine pancreas secretion at the status of hyperinsulinemia. The results showed that in normal man the degree of suppression of pancreatic glucagon secretion by hyperinsulinemia (approximately 100 uU/ml) during euglycemic glucose clamp without SRIF infusion was less than that of C-peptide with mean value of 62 +/- 4% of basal glucagon remained at the end of clamp study; while only about 30 +/- 2% of basal C-peptide concentrations remained. But during SRIF infused glucose clamp studies (SRIF was infused from 60 to 120 min), 32 +/- 2% of mean basal C-peptide concentrations and 38 +/- 6% of mean basal glucagon concentrations left at the end of 2 hr clamp studies when serum insulin level was about 100 uU/ml. For the glucose infusion rate (M value), it was significantly greater in our normal subjects in response to insulin + SRIF as compared to insulin alone (12.0 + 0.9 vs 8.8 +/- 1.4; P less than 0.01). We concluded: during hyperinsulinemia (100 uU/ml), the sensitivity of pancreatic alpha cells to insulin seems less than that of beta cells in normal man at normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes

For many years, the development of insulin resistance has been seen as the core defect responsible for the development of Type 2 diabetes. However, despite extensive research, the initial factors responsible for insulin resistance development have not been elucidated. If insulin resistance can be overcome by enhanced insulin secretion, then hyperglycaemia will never develop. Therefore, a β-cell defect is clearly required for the development of diabetes. There is a wealth of evidence to suggest that disorders in insulin secretion can lead to the development of decreased insulin sensitivity. In this review, we describe the potential initiating defects in Type 2 diabetes, normal pulsatile insulin secretion and the effects that disordered secretion may have on both β-cell function and hepatic insulin sensitivity. We go on to examine evidence from physiological and epidemiological studies describing β-cell dysfunction in the development of insulin resistance. Finally, we describe how disordered insulin secretion may cause intracellular insulin resistance and the implications this concept has for diabetes therapy. In summary, disordered insulin secretion may contribute to development of insulin resistance and hence represent an initiating factor in the progression to Type 2 diabetes.     

Evidence for unimpaired pancreatic secretion and hepatic removal of insulin in healthy offspring of type 2 (noninsulin-dependent) diabetic couples

The aim of the present study was to investigate the secretion and the hepatic removal of insulin in a group of 14 unaffected offspring of 14 type 2 (noninsulin-dependent) diabetic couples compared to 14 healthy subjects without family history of diabetes mellitus. The two groups, each consisting of 5 obese and 9 nonobese subjects, were carefully matched for sex, age, and body weight. We examined glucose, insulin, and C-peptide levels, as well as C-peptide to insulin ratios and relations during the oral glucose tolerance test. Glucose concentrations and incremental areas were similar in the two groups, as well as insulin and C-peptide levels and areas. C-peptide to insulin molar ratios, both in fasting state and after glucose load, as well as relations between C-peptide and insulin incremental areas were not different. Our results suggest that the healthy offspring of type 2 diabetic couples have a normal response of beta-cell to oral glucose as well as a normal removal of insulin by the liver.     

The course of development of glucose intolerance in the monkey (Macaca mulatta).

Longitudinal studies of the rhesus monkey reveal a syndrome of diabetes mellitus in those that become middle-aged and obese. The sequence of events in the development of the disease progresses from normoinsulinemia with normoglycemia through stages of hyperinsulinemia followed by below normal insulin levels with hyperglycemia and glycosuria. We believe the rhesus to be an excellent nonhuman primate model for maturity-onset diabetes in humans.     

Behavior of C-peptide and immunoreactive insulin in essential obesity]

The levels of glucose, immunoreactive insulin and C-peptide were studied in 13 obese patients and 10 control subjects, in basal conditions and after an oral glucose load (OGTT). The IRI and C-peptide levels were higher in the obese patients than in the controls either during fasting or during the OGTT. The C-peptide/IRI ratio decreased after the oral glucose load in both groups studied. However in the obese subjects the values for the C-peptide/IRI ratio were lower than those found in the controls during the same observation period. These results suggest the hypothesis that in the obese patients the high IRI levels which reflect an increased insulin secretion, are, at least in part, due to an early saturation of the hepatic degradation of insulin and/or to a decrease in the specific receptor sites normally present in the cell membranes.     

Dietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr

In a longitudinal study of the effects of moderate (70%) dietary restriction (DR) on aging, plasma glucose and insulin concentrations were measured from semiannual, frequently sampled intravenous glucose tolerance tests (FSIGTT) in 30 adult male rhesus monkeys. FSIGTT data were analyzed with Bergman's minimal model, and analysis of covariance revealed that restricted (R) monkeys exhibited increased insulin sensitivity (S(I), P < 0.001) and plasma glucose disappearance rate (K(G), P = 0.015), and reduced fasting plasma insulin (I(b), P < 0.001) and insulin response to glucose (AIR(G), P = 0.023) compared with control (C; ad libitum-fed) monkeys. DR reduced the baseline fasting hyperinsulinemia of two R monkeys, whereas four C monkeys have maintained from baseline, or subsequently developed, fasting hyperinsulinemia; one has progressed to diabetes. Compared with only the normoinsulinemic C monkeys, R monkeys exhibited similarly improved FSIGTT and minimal-model parameters. Thus chronic DR not only has protected against the development of insulin resistance in aging rhesus monkeys, but has also improved glucoregulatory parameters compared with those of otherwise normoinsulinemic monkeys.     

Islet protective and insulin secretion property of Murraya koenigii and Ocimum tenuflorum in streptozotocin-induced diabetic mice

The present study investigates the antidiabetogenic effects of Murraya koenigii (L.) Spr. and Ocimum tenuflorum L. on streptozotocin-induced diabetic Swiss mice. Treatment with extracts of M. koenigii (chloroform; MKC) and O. tenuflorum (aqueous; OTA) resulted in proper glucose utilization with an increase in liver glucose-6-phosphate dehydrogenase enzyme activity, and normal glycogenesis in hepatic and muscle tissues. Pancreatic and intestinal glucosidase inhibitory activity observed with MKC and OTA treatment indicated beneficial effects in reducing postprandial hyperglycemia with concomitant improvement in glucose metabolism. The glucosidase inhibition was prolonged, even after discontinuation of MKC and OTA treatment. Normalization of plasma insulin and C-peptide levels was observed in diabetic mice, indicating endogenous insulin secretion after treatment. The histochemical and immunohistochemical analysis of pancreatic islets suggests the role of MKC and OTA in pancreatic β-cell protection and the functional pancreatic islets that produce insulin. The study demonstrates the significance of MKC and OTA in glucosidase inhibition and islet protection in the murine diabetic model. These findings suggest the potential of the extracts in adjuvant therapy for the treatment of diabetes and the possible development of potential neutraceuticals.     

Plasma beta-endorphin in response to oral glucose tolerance test in obese patients

In order to clarify the possible interaction between endogenous opioids and glucose homeostasis in obesity we studied Beta-Endorphin (B-Ep), ACTH, cortisol and insulin plasma levels in response to an oral glucose tolerance test (OGTT) in 8 females suffering from uncomplicated obesity and in 6 healthy volunteers of normal weight. Results were evaluated in terms of secretion areas subtracted from basal value. Basal glucose, insulin and B-Ep levels were significantly higher in the obese patients compared to controls, cortisol levels and ACTH were not statistically different between obese and normal subjects. During OGTT total areas of insulin secretion were significantly higher in the obese patients; cortisol, ACTH, B-Ep plasma levels did not change in controls, whereas obese patients showed a response to B-Ep which reached a peak at 60 minutes. The area of B-Ep response to OGTT in obese patients was significantly higher than in controls. On the basis of these results we may suggest that the opioid system belongs to the chain of neuroendocrine and metabolic events responsible for the origin and the growth of overweight. But the possibility exists that obesity itself can enhance the B-Ep secretion above all through overeating. In this regard it is to stress that glucose ingestion induces in obese patients, differently from normal subjects, insulin hypersecretion and the B-Ep secretion, possibly from gastro-enteric tract and/or pancreatic isles.     

Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion

The G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β-cells. On activation, this receptor enhances the effect of glucose-stimulated insulin secretion (GSIS) via the elevation of intracellular cAMP concentrations. Although GPR119 agonists represent promising oral antidiabetic agents for the treatment of type 2 diabetes therapy, they suffer from the inability to adequately directly preserve β-cell function. To identify a new structural class of small-molecule GPR119 agonists with both GSIS and the potential to preserve β-cell function, we screened a library of synthetic compounds and identified a candidate molecule, AS1269574, with a 2,4,6-tri-substituted pyrimidine core. Here, we examined the preliminary in vitro and in vivo effects of AS1269574 on insulin secretion and glucose tolerance. AS1269574 had an EC₅₀ value of 2.5 μM in HEK293 cells transiently expressing human GPR119 and enhanced insulin secretion in the mouse pancreatic β-cell line MIN-6 only under high-glucose (16.8 mM) conditions. This contrasted with the action of the sulfonylurea glibenclamide, which also induced insulin secretion under low-glucose conditions (2.8 mM). In in vivo studies, a single administration of AS1269574 to normal mice reduced blood glucose levels after oral glucose loading based on the observed insulin secretion profiles. Significantly, AS1269574 did not affect fed and fasting plasma glucose levels in normal mice. Taken together, these results suggest that AS1269574 represents a novel structural class of small molecule, orally administrable GPR119 agonists with GSIS and promising potential for the treatment of type 2 diabetes.     

Beta-cell "rest" accompanies reduced first-pass hepatic insulin extraction in the insulin-resistant, fat-fed canine model

During insulin resistance, glucose homeostasis is maintained by an increase in plasma insulin via increased secretion and/or decreased first-pass hepatic insulin extraction. However, the relative importance of insulin secretion vs. clearance to compensate for insulin resistance in obesity has yet to be determined. This study utilizes the fat-fed dog model to examine longitudinal changes in insulin secretion and first-pass hepatic insulin extraction during development of obesity and insulin resistance. Six dogs were fed an isocaloric diet with an approximately 8% increase in fat calories for 12 wk and evaluated at weeks 0, 6, and 12 for changes in 1) insulin sensitivity by euglycemic-hyperinsulinemic clamp, 2) first-pass hepatic insulin extraction by direct assessment, and 3) glucose-stimulated insulin secretory response by hyperglycemic clamp. We found that 12 wk of a fat diet increased subcutaneous and visceral fat as assessed by MR imaging. Consistent with increased body fat, the dogs exhibited a approximately 30% decrease in insulin sensitivity and fasting hyperinsulinemia. Although insulin secretion was substantially increased at week 6, beta-cell sensitivity returned to prediet levels by week 12. However, peripheral hyperinsulinemia was maintained because of a significant decrease in first-pass hepatic insulin extraction, thus maintaining hyperinsulinemia, despite changes in insulin release. Our results indicate that when obesity and insulin resistance are induced by an isocaloric, increased-fat diet, an initial increase in insulin secretion by the beta-cells is followed by a decrease in first-pass hepatic insulin extraction. This may provide a secondary physiological mechanism to preserve pancreatic beta-cell function during insulin resistance.     

Rethinking leptin and insulin action: therapeutic opportunities for diabetes

Leptin is an adipocyte-derived hormone that primarily acts in the hypothalamus and plays a key role in the regulation of food intake, body weight, energy expenditure and neuroendocrine function. Leptin has direct peripheral effects on several tissues, and it may be independently involved in insulin secretion and action besides its effects on body weight regulation. Basal plasma leptin and insulin concentrations correlate with each other. Insulin and glucose appear to increase leptin secretion. In turn, leptin increases peripheral insulin sensitivity while decreasing insulin secretion from pancreatic beta cells. Leptin increases skeletal muscle glucose uptake and oxidation, and suppresses hepatic glucose output. Effects of leptin on lipid metabolism might reduce lipotoxicity and therefore contribute to the improvement of hepatic, skeletal and whole body insulin sensitivity. Leptin is the first adipokine used in the treatment of hypoleptinemic clinical disorders. Although leptin therapy has limited success in common obesity, it has impressive effects in congenital leptin deficiency, lipoatrophic diabetes and syndromes of severe insulin resistance. Leptin has been reported to ameliorate hyperinsulinemia and diabetes in the clinical setting of congenital leptin deficiency. It also improves hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia and hepatic steatosis in lipoatrophic diabetes. These promising results warrant clinical trials to test the hypothesis that leptin alone or with classical antidiabetic agents may potentially be beneficial in the treatment of hypoleptinemic non-obese individuals with glucose intolerance and diabetes. This review summarizes the clinical applications of leptin, particularly emphasizing the effects of leptin on glucose homeostasis.     

Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Islet damage from glucose toxicity is implicated in the pathogenesis of type 2 diabetes, but the sequence of events leading to islet cell dysfunction and hyperglycemia remains unclear. To examine the early stages of islet pathology resulting from increased basal glucose loads, normal awake rats were infused with glucose continuously for 10 days. Plasma glucose and markers of islet and liver function were monitored throughout the infusion. After initial hyperglycemia, rats adapted to the infusion and maintained euglycemia for approximately 4 days. Continued infusion led to worsening hyperglycemia in just 5% of rats after 6 days, but 69% after 8 days and 89% after 10 days, despite unchanged basal and stimulated plasma insulin and C-peptide concentrations. In contrast, plasma glucagon concentrations increased fivefold. Endogenous glucose production (EGP) was appropriately suppressed after 4 days (2.8 ± 0.7 vs. 6.1 ± 0.4 mg·kg(-1)·min(-1) on day 0, P < 0.001) but tripled between days 4 and 8 (9.9 ± 1.7 mg·kg(-1)·min(-1), P < 0.01). Surprisingly, the increase in EGP was accompanied by increased mitochondrial phosphoenolpyruvate carboxykinase expression with appropriate suppression of the cytosolic isoform. Infusion of anti-glucagon antibodies normalized plasma glucose to levels identical to those on day 4 and ～300 mg/dl lower than controls. This improved glycemia was associated with a 60% reduction in EGP. These data support the novel concept that glucose toxicity may first manifest as α-cell dysfunction prior to any measurable deficit in insulin secretion. Such hyperglucagonemia could lead to excessive glucose production overwhelming the capacity of the β-cell to maintain glucose homeostasis.