Human Insulin Microcrystals with Lactose Carriers for Pulmonary Delivery

Dry powder formulations for pulmonary delivery are attractive because many issues of solubility and stability can be minimized. Human insulin microcrystals with lactose carriers were produced for pulmonary delivery. The average particle diameter was 2.3 μm, with a narrow, monodispersed size distribution. The percentages of high molecular weight proteins (%HMWPs), other insulin-related compounds (%OIRCs), and A-21 desamido insulin (%D_es) were very low throughout the microcrystal preparation process. Administration of the microcrystal powder by intratracheal insufflation significantly reduced the blood glucose levels of Sprague-Dawley rats. The percent minimum reductions of the blood glucose concentration (%MRBG) produced by the insulin microcrystal powder and by an insulin solution reached 40.4% and 33.4% of the initial glucose levels respectively, and their bioavailability relative to subcutaneous injection (F) was 15% and 10% respectively. These results confirm that the insulin microcrystal powder prepared is suitable for pulmonary delivery in an effective dosage form.     

Synthesis and characterization of alginate coated zinc calcium phosphate nanoparticles for intestinal delivery of insulin

Nanosized calcium phosphates studied as drug delivery systems are highly compatible with the various drugs like insulin, antibiotics etc. Zinc is an essential trace element that plays a crucial role in the synthesis, storage and release of insulin in a human body. Therefore, an attempt has been made to develop zinc modified calcium phosphate nanoparticles (less than 100 nm) as carriers for intestinal delivery of insulin. The insulin loaded nanoparticles were coated with pH sensitive alginate. These pH sensitive nanoparticles released insulin in the intestinal medium, and the conformation of released insulin was stable. The blood glucose level of diabetic rats came to normal on administration of the formulation. With the beneficial effect of zinc reported on diabetic patients, the present system seems to be an excellent carrier for intestinal delivery of insulin.     

Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection

Prior studies have demonstrated the effectiveness of noninvasive transdermal insulin delivery using a cymbal transducer array. In this study the physiologic response to ultrasound mediated transdermal insulin delivery is compared to that of subcutaneously administered insulin. Anesthetized rats (350-550 g) were divided into four groups of four animals; one group representing ultrasound mediated insulin delivery and three representing subcutaneously administered insulin (0.15, 0.20, and 0.25 U/kg). The cymbal array was operated for 60 minutes at 20 kHz with 100 mW/cm2 spatial-peak temporal-peak intensity and a 20% duty cycle. The blood glucose level was determined at the beginning of the experiment and, following insulin administration, every 15 minutes for 90 minutes for both the ultrasound and injection groups. The change in blood glucose from baseline was compared between groups. When administered by subcutaneous injection at insulin doses of 0.15 and 0.20 U/kg, there was little change in the blood glucose levels over the 90 minute experiment. Following subcutaneous administration of insulin at a dose of 0.25 U/kg, blood glucose decreased by 190 +/- 96 mg/dl (mean +/- SD) at 90 minutes. The change in blood glucose following ultrasound mediated insulin delivery was -262 +/- 40 mg/dl at 90 minutes. As expected, the magnitude of change in blood glucose between the three injection groups was dependant on the dose of insulin administered. The change in blood glucose in the ultrasound group was greater than that observed in the injection groups suggesting that a higher effective dose of insulin was delivered.     

Glucose tolerance, plasma and pancreatic insulin levels in zinc deficient rats.

Two experiments were conducted to examine the effect of zinc deficiency on glucose tolerance, and on blood and pancreatic insulin concentrations. In the first study, no significant differences in blood glucose or plasma insulin levels were noted between pair-weighted zinc deficient and zinc sufficient rats after an oral glucose load. In the second experiment, the concentration of pancreatic insulin in pair-fed zinc sufficient rats did not differ significantly from that of zinc deficient rats. However, a zinc deficient group fed ad libitum had significantly lower pancreatic insulin levels, suggesting that food restriction may cause increased pancreatic insulin. Thus, zinc deficiency per se had no apparent effect on oral glucose tolerance or pancreatic insulin concentrations.     

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.     

Zinc Supplementation Does Not Affect Glucagon Response to Intravenous Glucose and Insulin Infusion in Patients with Well-Controlled Type 2 Diabetes

Glucagon dysregulation is an essential component in the pathophysiology of type 2 diabetes. Studies in vitro and in animal models have shown that zinc co-secreted with insulin suppresses glucagon secretion. Zinc supplementation improves blood glucose control in patients with type 2 diabetes, although there is little information about how zinc supplementation may affect glucagon secretion. The objective of this study was to evaluate the effect of 1-year zinc supplementation on fasting plasma glucagon concentration and in response to intravenous glucose and insulin infusion in patients with type 2 diabetes. A cross-sectional study was performed after 1-year of intervention with 30 mg/day zinc supplementation or a placebo on 28 patients with type 2 diabetes. Demographic, anthropometric, and biochemical parameters were determined. Fasting plasma glucagon and in response to intravenous glucose and insulin infusion were evaluated. Patients of both placebo and supplemented groups presented a well control of diabetes, with mean values of fasting blood glucose and glycated hemoglobin within the therapeutic goals established by ADA. No significant differences were observed in plasma glucagon concentration, glucagon/glucose ratio or glucagon/insulin ratio fasting, after glucose or after insulin infusions between placebo and supplemented groups. No significant effects of glucose or insulin infusions were observed on plasma glucagon concentration. One-year zinc supplementation did not affect fasting plasma glucagon nor response to intravenous glucose or insulin infusion in well-controlled type 2 diabetes patients with an adequate zinc status.     

Effects of zinc supplementation on the plasma glucose level and insulin activity in genetically obese (ob/ob) mice

The effects of zinc supplementation (20 mM ZnCl₂ from the drinking water for eight weeks) on plasma glucose and insulin levels, as well as its in vitro effect on lipogenesis and lipolysis in adipocytes were studied in genetically obese (ob/ob) mice and their lean controls (+/?). Zinc supplementation reduced the fasting plasma glucose levels in both obese and lean mice by 21 and 25%, respectively (p < 0.05). Fasting plasma insulin levels were significantly decreased by 42% in obese mice after zinc treatment. In obese mice, zinc supplementation also attenuated the glycemic response by 34% after the glucose load. The insulin-like effect of zinc on lipogenesis in adipocytes was significantly increased by 80% in lean mice. However, the increment of 74% on lipogenesis in obese mice was observed only when the zinc plus insulin treatment was given. This study reveals that zinc supplementation alleviated the hyperglycemia of ob/ob mice, which may be related to its effect on the enhancement of insulin activity.     

Levels of Zn and Cu in the serum of a diabetic population

The zinc and copper content in serum as well as glucose and insulin was determined in 140 diabetics and compared with the results obtained from 162 healthy patients. Their mean values are significantly different. Each group was classified accordingly to the presence or not of overweight (greater than 15% relative body weight). The correlations (Pearson. Anova) between the different parameters in each group were studied. Healthy group showed a negative correlationship between the zinc and insulin levels and between the latter and the copper level, and a positive one between copper and every other parameter. Obesity only affected the zinc levels in diabetics and increased them in a statistically significant way. In this group, the copper level showed a positive correlation with the zinc level and the latter with the glucose. Owing to these results zinc and copper levels seem to be directly correlated and in diabetic patients these levels are increased mainly in the case of obesity. In healthy patients zinc levels are correlated with serum insulin, and in the diabetic groups with serum glucose.     

Insulin replacement therapy for the rat model of streptozotocin-induced diabetes mellitus

OBJECTIVE: This study was conducted to compare various strategies for insulin replacement therapy in the streptozotocin-induced diabetic rat model. METHODS: Control and diabetic Sprague Dawley rats were fed ad libitum, blood glucose concentration was measured twice daily, and outcome was assessed over the final 5 days of a 10-day treatment period, with adjustment of insulin dosage toward the goal of normal glucose values. RESULTS: All insulin regimens induced weight gain at least comparable to that of controls, but glucose regulation differed. It was not possible to normalize glucose values by use of protamine zinc insulin (PZI) or Ultralente insulin given once daily. In contrast, PZI and neutral protamine Hagedorn (NPH) insulin given twice daily provided glucose values comparable to those in controls, whereas glucose values were modestly higher in response to a 70% human insulin isophane suspension and 30% soluble human insulin solution (70/ 30 insulin) given twice daily. Attempted normalization of glucose values was limited by hypoglycemia, which was most common after administration of PZI once daily, and least common after 70/30 insulin given twice daily. Dosage requirements for Ultralente insulin were four- to fivefold higher than those for all other insulins. CONCLUSION: In streptozotocin-diabetic rats, normal weight gain can be achieved by treatment with PZI insulin once daily, but attainment of near-normal glucose values requires administration of PZI, NPH, or 70/ 30 insulin twice daily. Ultralente insulin may have reduced bioeffectiveness in this animal model.     

Metabolic studies during normoglycaemic clamping of insulin-dependent diabetics using a glucose-controlled insulin infusion system.

Metabolic rhythms have been studied in six insulin-dependent diabetics during subcutaneous insulin therapy, and during control of blood glucose concentration by a glucose-controlled insulin infusion system (GCIIS). In none of the subjects was blood glucose concentration consistently within the normal range during subcutaneous insulin therapy. In contrast, blood glucose concentration was within the normal range after 3.5 h of insulin delivery by the glucose-controlled insulin infusion system and remained in the normal range for the following 8 h through lunch and dinner. Mean blood glucose concentration during this time ranged from 5.31 to 7.90 mM. Following normalisation of blood glucose concentration, blood lactate and pyruvate were similar with both the GCIIS and subcutaneous insulin therapy. Post-prandial lactate peaks were delayed with the GCIIS. Alanine levels were consistently higher during control with the GCIIS compared with subcutaneous therapy, while blood ketone body and plasma NEFA levels were lower, and the premeal peaks in the lipid metabolites were delayed. It is not possible to conclude that attainment of normoglycaemia with the present generation of glucose-controlled insulin infusion systems in insulin-dependent diabetics is accompanied by total normalisation of intermediary metabolism.     

Zinc and insulin metabolism

A review of experimental studies of the effect of zinc nutrition on insulin metabolism is presented. In addition to a short introduction to the synthesis, secretion, and action of insulin, the effects of zinc deficiency—specifically on glucose tolerance, insulin secretion, insulin synthesis and storage, and on total insulin-like activity—are dealt with. The concentrations of zinc and chromium in serum, pancreas, and liver are compared to those of zinc-deficient animals and pair-fed controls. In contrast to pair-fed controls, zinc-deficient rats had unaltered proinsulin contents after glucose stimulation, but they showed a diminished glucose tolerance, lowered serum insulin content, and an elevated total insulin-like activity. The serum zinc concentration of the deficient animals was greatly reduced and did not change during glucose stimulation, whereas it rose in the case of the pair-fed controls. The serum chromium concentration increased in both groups in response to glucose stimulation. In the pancreas of the deficient animals, the zinc concentration was reduced 60% and it increased during the glucose tolerance test. In the liver there were no significant differences. The chromium concentrations were elevated in both the pancreas and liver of the zinc-deficient rats by 60 and 100%, respectively, and were not influenced by glucose injection. These studies show clearly that nutritional zinc deficiency influences insulin metabolism and action.     

Effect of Sub-deficient Zinc Status on Insulin Sensitivity after Burn Injury in Rats

Although zinc status is an important parameter in insulin sensitivity, data concerning its implication in noxious burn-induced insulin resistance are scarce. The present study was designed to evaluate the impact of zinc status before burn on the recovery of injury with focus on plasma insulin and glucose levels. The experiment was performed in male adult Wistar rats fed from weaning with a zinc normal diet (80 ppm) or a depleted zinc diet (10 ppm) for 8 weeks and burned to third degree on 20% of their total body surface area. Blood and tissue samples were collected 3, 6, and 24 h after injury in order to study biochemical parameters and the glucose/insulin response in relation with the zinc status. After burn, zinc-depleted rats presented an exacerbated decrease in plasma zinc level. In addition, the burn-induced insulin resistance, leading to protein catabolism, was emphasized, with higher plasma insulin, glucose, and leptin levels in zinc-deficient animals versus normal-fed rats. Our experimental results underlined the interest to early control the zinc status in order to limit the deleterious effects of oxidative stress and insulin resistance in burned patients.     

Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle

Insulin has an exercise-like action to increase microvascular perfusion of skeletal muscle and thereby enhance delivery of hormone and nutrient to the myocytes. With insulin resistance, insulin's action to increase microvascular perfusion is markedly impaired. This review examines the present status of these observations and techniques available to measure such changes as well as the possible underpinning mechanisms. Low physiological doses of insulin and light exercise have been shown to increase microvascular perfusion without increasing bulk blood flow. In these circumstances, blood flow is proposed to be redirected from the nonnutritive route to the nutritive route with flow becoming dominant in the nonnutritive route when insulin resistance has developed. Increased vasomotion controlled by vascular smooth muscle may be part of the explanation by which insulin mediates an increase in microvascular perfusion, as seen from the effects of insulin on both muscle and skin microvascular blood flow. In addition, vascular dysfunction appears to be an early development in the onset of insulin resistance, with the consequence that impaired glucose delivery, more so than insulin delivery, accounts for the diminished glucose uptake by insulin-resistant muscle. Regular exercise may prevent and ameliorate insulin resistance by increasing "vascular fitness" and thereby recovering insulin-mediated capillary recruitment.     

Dietary Intake and Serum and Hair Concentrations of Minerals and their Relationship with Serum Lipids and Glucose Levels in Hypertensive and Obese Patients with Insulin Resistance

Inadequate minerals intake, as well as disruption of some metabolic processes in which microelements are cofactors, are suggested to lead to the development of hypertension. The role of minerals in the pathogenesis of hypertension still remains to be explained. In the present study, we sought to determine associations between serum and hair mineral concentrations and serum lipids and glucose levels. Forty obese hypertensive subjects with insulin resistance and 40 healthy volunteers were recruited in the study. Blood pressure, BMI, and insulin resistance were recorded in all subjects. Levels of lipids, glucose, sodium and potassium, iron, copper, zinc, magnesium, and calcium were assessed in serum. Iron, copper, zinc, magnesium, and calcium were assessed in hair. Dietary intake of the analyzed minerals was estimated. We found distinctly higher concentrations of serum iron and serum and hair calcium as well as markedly lower levels of hair zinc in the hypertensive subjects. The study group manifested also significantly lower daily intake of calcium, magnesium, and iron. We observed a relationship between the concentrations of iron, zinc, and copper in serum and hair and high and low range of cholesterol, triglycerides, and glucose serum levels in the studied patients. Moreover, this study demonstrated significant correlation between serum and hair concentrations of selected minerals and their dietary intake and levels of serum lipids and glucose and blood pressure in the study and the control groups. The obtained results seem to indicate the association between lipid and glucose metabolism and iron, copper, zinc, and calcium concentrations in blood and hair of hypertensive and obese patients with insulin resistance.     

Seven days of aerobic exercise training improves conduit artery blood flow following glucose ingestion in patients with type 2 diabetes

The vasodilatory effects of insulin account for up to 40% of insulin-mediated glucose disposal; however, insulin-stimulated vasodilation is impaired in individuals with type 2 diabetes, limiting perfusion and delivery of glucose and insulin to target tissues. To determine whether exercise training improves conduit artery blood flow following glucose ingestion, a stimulus for increasing circulating insulin, we assessed femoral blood flow (FBF; Doppler ultrasound) during an oral glucose tolerance test (OGTT; 75 g glucose) in 11 overweight or obese (body mass index, 34 ± 1 kg/m2), sedentary (peak oxygen consumption, 23 ± 1 ml·kg?1·min?1) individuals (53 ± 2 yr) with non-insulin-dependent type 2 diabetes (HbA1c, 6.63 ± 0.18%) before and after 7 days of supervised treadmill and cycling exercise (60 min/day, 60-75% heart rate reserve). Fasting glucose, insulin, and FBF were not significantly different after 7 days of exercise, nor were glucose or insulin responses to the OGTT. However, estimates of whole body insulin sensitivity (Matsuda insulin sensitivity index) increased (P < 0.05). Before exercise training, FBF did not change significantly during the OGTT (1 ± 7, -7 ± 5, 0 ± 6, and 0 ± 5% of fasting FBF at 75, 90, 105, and 120 min, respectively). In contrast, after exercise training, FBF increased by 33 ± 9, 39 ± 14, 34 ± 7, and 48 ± 18% above fasting levels at 75, 90, 105, and 120 min, respectively (P < 0.05 vs. corresponding preexercise time points). Additionally, postprandial glucose responses to a standardized breakfast meal consumed under "free-living" conditions decreased during the final 3 days of exercise (P < 0.05). In conclusion, 7 days of aerobic exercise training improves conduit artery blood flow during an OGTT in individuals with type 2 diabetes.     

Influence of vasoactive intestinal polypeptide (VIP) on splanchnic and central hemodynamics in healthy subjects

The influence of VIP, a potent vasodilator, on central hemodynamics, splanchnic blood flow and glucose metabolism was studied in six healthy subjects. Teflon catheters were inserted into an artery, a femoral vein and a right-sided hepatic vein. A Swan-Ganz catheter was introduced percutaneously and its tip placed in the pulmonary artery. Determinations of cardiac output, systemic, pulmonary arterial and hepatic venous pressures as well as splanchnic blood flow were made in the basal state and at the end of two consecutive 45 min periods of VIP infusion at 5 and 10 ng/kg/min, respectively. Arterial blood samples for analysis of glucose, FFA, insulin and glucagon were drawn at timed intervals. VIP infusion at 5 ng/kg/min resulted in an increase in cardiac output (55%) and heart rate (25%) as well as a reduction in mean systemic arterial pressure (15%) and vascular resistance (45%). With the higher rate of VIP infusion heart rate tended to rise further while cardiac output and arterial pressure remained unchanged. At 15 min after the end of VIP infusion the above variables had returned to basal levels. Splanchnic blood flow and free hepatic venous pressure did not change significantly. Arterial concentrations of glucose, FFA, insulin and glucagon increased during VIP infusion. At 15 min after the end of infusion the glucose levels were still significantly higher than basal (20%). Net splanchnic glucose output did not change in response to VIP infusion. It is concluded that VIP exerts a potent vasodilatory effect resulting in augmented cardiac output and lowered systemic blood pressure and vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antidiabetic and Pancreas-Protective Effects of Zinc Threoninate Chelate in Diabetic Rats may be Associated with its Antioxidative Stress Ability

Zinc exerts a wide range of important biological roles. The present study was carried out to investigate the effects of zinc threoninate chelate in blood glucose levels, lipid peroxidation, activities of antioxidant defense systems and nitrite concentration, and histology of the pancreas in diabetic rats. Wistar rats were intravenously injected with a single dose of streptozotocin to induce diabetes. Then, diabetic rats were administrated orally with zinc threoninate chelate (3, 6, and 9 mg/kg body weight) once daily for 7 weeks. Fasting blood glucose was monitored weekly. At the end of the experimental period, the diabetic rats were killed, and levels of serum insulin, malondialdehyde, and nitric oxide, activities of glutathione peroxidase, total superoxide dismutase, copper/zinc-superoxide dismutase, and nitric oxide synthase were determined; pancreas was examined histopathologically as well. Zinc threoninate chelate significantly reduced the blood glucose levels and significantly increased the serum insulin levels in diabetic rats. In addition, zinc threoninate chelate caused a significant increase in activities of antioxidant enzymes and significant decrease in nitrite concentration and malondialdehyde formation in the pancreas and serum of diabetic rats. These biochemical observations were supplemented by histopathological examination of the pancreas. These results suggested that the antidiabetic effect of zinc threoninate chelate may be related to its antioxidative stress ability in diabetic rats.     

A glucose-controlled insulin infusion system for diabetic women during labour.

A glucose-controlled insulin infusion system was used to control blood glucose concentration during labour or caesarean section in six insulin-dependent diabetics. The mean blood glucose concentration during the four hours of labour immediately before delivery was 4.6-5.2 mmol/1 (82.9-93.7 mg/100 ml). Feedback control of insulin delivery by blood glucose concentration should decrease the risk of postpartum hypoglycaemia in the infant and allow normal obstetric management for the insulin-dependent diabetic in labour.     

Characterization of the portal signal during 24-h glucose delivery in unrestrained, conscious rats

To characterize the "portal signal" during physiological glucose delivery, liver glycogen was measured in unrestrained rats during portal (Po) and peripheral (Pe) constant-rate infusion, with minimal differences in hepatic glucose load (HGL) and portal insulin between the delivery routes. Hepatic blood flows were measured by Doppler flowmetry during open surgery. Changes in hepatic glucose, portal insulin, glucagon, lactate, and free fatty acid concentrations were generally similar in either delivery except for glucagon at 4 h. Hepatic glycogen, however, increased continuously in Po and was higher than Pe at 8 and 24 h, although it decreased to the level of Pe upon the removal of Po at 8 h. There was a near-linear relationship between hepatic glycogen and HGL in either delivery, with the slope being twice as high in Po and the intercepts converging to basal HGL. The hepatic response to Po did not alter upon 80% replacement by Pe. These results suggest that negative arterial-portal glucose gradients increase the rate of hepatic glycogen synthesis against the incremental HGL in an all-or-nothing mode.     

Control of postprandial hyperglycaemia by galactosyl maltobionolactone and its novel anti-amylase effect in mice

The ability to control carbohydrate digestion is useful in the treatment of diabetes mellitus and obesity. In the present study, we examined whether recently developed 4(2)-O-beta-D-galactosyl maltobionolactone (LG2O) having anti-amylase activity is able to control postprandial blood glucose concentration in mice. In addition, we tried to determine how LG2O regulates carbohydrate delivery in the gut lumen by conducting in vivo and in vitro studies. Male non-diabetic ddY mice and KK-A(y) mice, a spontaneously diabetic strain, had free access to a carbohydrate rich diet supplemented with LG2O (3 or 10 g/kg) for 0.5 hr, and blood glucose concentration was measured. LG2O suppressed any steep increase in postprandial blood glucose concentration in both ddY and KK-A(y) mice. Corresponding to the blood glucose response, LG2O also markedly suppressed any increase in postprandial plasma insulin concentration. After ingestion of the diet, LG2O produced a 1.5-3.5 fold increase in the gut contents and reducible sugar content in the small intestine but not in the stomach. Although alpha-amylase activity in the stomach was much lower compared with the activity in the small intestine, LG2O still strongly inhibited alpha-amylase activity in the stomach. In contrast, LG2O had little or no influence on alpha-amylase activity in the proximal intestine. From the in vitro carbohydrate digestion stimulation, LG2O at 7.5 mM decreased glucose production by 75% for dextrin, 25% for alpha-starch and 60% for raw starch. In conclusion, administration of LG2O inhibits carbohydrate digestion in the gut, and produces significant improvements in both blood glucose and insulin response following ingestion as part of the diet, and this evidence provides support for its therapeutic potential in treating diabetes mellitus and obesity.