New Concepts in Diabetes and Its Treatment - part 3 docx

muscles, adipose tissue and hepatocytes, while normalizing a wide range of metabolic abnormalities associated with insulin resistance. Reported effects include: (a) decrease in plasma triglyceride, FFA and LDL cholesterol levels and increase in plasma HDL cholesterol; (b) increased expression of glucose transporters GLUT-1 and GLUT-4; (c) activation of glycolysis in hepatocytes; (d) antagonism towards some of the effects of TNF; (e) decrease in blood pressure; (f) inhibition of vascular smooth muscle cell proliferation and hypertrophy; (g) enhanced endothelium-dependent vasodilation, and (h) anti- oxidant action. Finally, although thiazolidinediones do not stimulate insulin secretion, they improve the secretory response of -cells to insulin secretagog- ues. Rosiglitazone (aPPARAgonist). Rosiglitazone, like other thiazolidine- dione compounds, is a PPAR agonist, inasmuch as it potently and specifically stimulates peroxisome proliferator-activated receptors- (PPAR) and sensi- tizes cells to insulin. Indeed, rosiglitazone is an antidiabetic agent which en- hances sensitivity to insulin in the liver, adipose tissue and muscle, resulting in increased insulin-mediated glucose disposal. This compound, therefore, improves insulin resistance, which is a key underlying metabolic abnormality in most patients with type 2 diabetes. In contrast with troglitazone, rosiglita- zone does not appear to be hepatotoxic, on the basis of clinical and in vitro studies, and does not induce cytochrome P 450 3A4 metabolism. However, the drug is contraindicated in patients with history or signs/symptoms of liver diseases and its use requires monitoring of liver function tests. Moreover, rosiglitazone doesnot interactsignificantly with nifedipine, oral contraceptives, metformin, digoxin, ranitidine, or acarbose. In clinical trials, rosiglitazone 2–12 mg/day (as single daily dose or two divided daily doses) improved glycemic control in type 2 diabetic patients, as shown by decrease in fasting plasma glucose and glycated hemoglobin (HbA 1c ). Addition of rosiglitazone 2–8 mg/day to existing sulfonylurea, met- formin or insulin therapy achieved reductions in fasting plasma glucose and HbA 1c . Consistent with its mechanism of action, rosiglitazone appears to be associated with a low risk of hypoglycemia (=2% of patients receiving mono- therapy) and did not increase the risk of alcohol-induced hypoglycemia. Other Compounds The long-acting, nonsulfhydryl-containing ACE inhibitor, trandolapril, alone and in combination with the Ca 2+ -channel blocker, verapamil, can sig- nificantly improve whole-body glucose metabolism by acting on the insulin- 54Belfiore/Iannello sensitive skeletal muscle glucose transport system in obese Zucker rats. Data on the role of TNF raise the possibility that pharmacological inhibition of this factor may provide a novel therapeutic target to treat patients with type 2 diabetes. Suggested Reading American Diabetes Association: Consensus Development Conference on Insulin Resistance, Nov 5–6, 1997. Diabetes Care 1998;21:310–314. Bell PM, Hadden DR: Metformin. Endocrinol Metab Clin North Am 1997;26:523–537. Scheen AJ: Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996;30:359–371. Daniel JR, Hagmeyer KO: Metformin and insulin: Is there a role for combination therapy? Ann Pharma- cother 1997;31:474–480. Davidson MB, Peters AL: An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997;102:99–110. DeFronzo RA, Bonadonna RC, Ferrannini E: Pathogenesis of NIDDM: A balanced overview. Diabetes Care 1992;15:318–368. Melchior WR, Jaber LA: Metformin: An antihyperglycemic agent for treatment of type II diabetes. Ann Pharmacother 1996;30:158–164. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865. F. Belfiore, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, I–95123 Catania (Italy) Tel. +39 095 330981, Fax +39 095 310899, E-Mail francesco.belfiore@iol.it 55Insulin Resistance and Its Relevance to Treatment Chapter IV Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 56–71 Diet and Modification of Nutrient Absorption S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy Diet Introduction In the treatment of diabetes mellitus, changes in lifestyle play a major role, in addition to treatment with insulin or oral glucose-lowering drugs. For most patients with type 2 diabetes, the changes in lifestyle (concerning diet and exercise) are the cornerstone of treatment whereas the pharmacologic intervention represents a supplementary treatment for those patients who do not respond adequately to lifestyle changes. Dietary caloric restriction ameliorates hyperinsulinemia and hyperglyce- mia in obese type 2 diabetics (and improves other metabolic parameters; see table 1) and reduces the incidence of type 2 diabetes in subjects at risk or with impaired glucose tolerance (IGT). Glucose tolerance and insulin sensitivity improve when normal body weight is achieved or approached. Indeed, even a 7–10% of weight loss is enough to improve insulin resistance in all obese type 2 diabetics. Nutritional needs are different in type 1 (lean) or type 2 (overweight or obese) diabetic patients. Diet education is crucial and requires the participation of the patient and its family in the planning-diet process and in the implementation of the adequate strategies to promote adherence to dietary intervention. Goals of dietary therapy in diabetes are to reach and maintain ideal body weight (IBW), to maintain fasting and postprandial glycemic levels as close as possible to normal andto achieve optimal blood lipid values, while providing adequate caloric intake as required for the various metabolic needs. 56 Table 1. Effects of weight loss on altered parameters in obese type 2 diabetics Insulin resistance Hyperglycemia Hypertriglyceridemia Total hypercholesterolemia LDL cholesterol HDL cholesterol ! Hypertension Modern recommended diet for diabetes is relatively high in complex carbo- hydrates (55–60% of total calories) and fibers, low in fats (25–30%) especially saturated (=10%, to reduce dyslipidemia and atherosclerosis associated to diabetes) and limited, but adequate, in proteins (15%). Body Weight and Fat Distribution Increase in body weight (related to height) or frank obesity are highly relevant to the pathogenesis of type 2 diabetes. The ‘ideal’ body weight (actually the weight associated with the lowest mortality) for each inch of height can be derived from the 1983 Metropolitan Life Insurance Weights for Heights tables, referring to 4.2 million subjects aged 20–59. For people over 55, the tables of median weights derived from the data of the National Health and Nutrition Examination Surveys (NHANES) may also be used. A commonly used parameter relating weight to height is the body mass index (BMI), which is calculated as follows: BMI>weight (kg)/height (m) 2 . In the clinical setting, a BMI from 20 to 25 can be regarded as ‘normal’ while a BMI ?27 can be regarded as indicative of overweight. In some studies, the following values have been suggested for the BMI: =23.9>normal value for women; =25> normal value for men; 23.9–28.6 (female) and 25–30 (male)>overweight; ?28.6 (female) or ?30 (male)>obesity. In 1995, the WHO established the following BMI values: normal>18.5–24.9; overweight, 1st degree>25.0–29.9; overweight, 2nd degree (or obesity)>30.0–39.9; overweight, 3rd degree (or severe obesity) P40. It should be noted that the BMI associated with the lowest mortality increases with age, ranging from =20 at age 20 to about 28 at age 70. It should be noted that from the above values of BMI it is possible to calculate the corresponding weight values through the formula: weight (kg)>BMI¶height (m) 2 . Assessment of adipose tissue distribution is of para- mount importance to distinguish between visceral (or central or abdominal 57Diet and Modification of Nutrient Absorption or android) obesity and subcutaneous (or gynoid) obesity. A largely used parameter is the the waist-to-hip ratio (WHR), i.e. the ratio between the circumference at the waist and that at hip level. The cut-off value distin- guishing normal from abnormal WHR has not yet been definitely established. In some studies, values of WHR ?0.81 for female and ?0.92 for male subjects were considered indicative of visceral/android obesity whereas lower WHR values were regarded as indicative of subcutaneous/gynoid obesity. The American Heart Association has reported that a WHR ?0.80 should be used to indicate increased risk of cardiovascular disease in women. Other recent data suggest an upward shift in the critical threshold for WHR to P0.90, at which point there is an elevation in cardiovascular disease risk factors. It has also been shown that the simple waist circumference is a good index of central (visceral) obesity, as is also the sagittal diameter. The values of waist circumference indicating increased visceral fat and cardiovascular risk were found to be ?94 cm in men and ?80 cm in women. Recently, it has been reported that, while a waist circumference P96.5 cm is associated with high cardiovascular risk, even a waist circumference P76.2 cm entails signifi- cant risk. Interestingly, threshold values of waist girth corresponding to critical amounts of visceral adipose tissue do not appear to be influenced by sex or by the degree of obesity. It has also been estimated that a waist girth of approximately 95 cm in both sexes, WHR values of 0.94 in men and of 0.88 in women, and sagittal diameters of 22.8 cm in men and 25.2 cm in women correspond to a critical amount of visceral adipose tissue, equal to a fat area of 130 cm 2 . The amount of intra-abdominal (visceral) fat may be precisely measured with computed tomography (CT), which however is an expensive procedure. Echography is also being used to quantify the fat tissue and its distribution. Total Caloric Requirement The caloric requirement of diabetic patients is similar to that of normal subjects and changes with age, sex and occupational daily work or physical activity (i.e. patients engaged in a heavy activity require a larger caloric intake). Other factors may influence dietary regimen, as the type of diabetes and the associated diseases. In lean adult diabetic patients, caloric intake should maintain a normal weight, while in obese diabetic patients (especially with upper body fat distribution) a caloric restriction is required to achieve a desirable weight. Noticeably, dietary restriction may improve metabolic control even before weight loss is attained. 58Iannello Sedentary normal patients need approximately 30 cal/kg IBW/day while active normal patients need approximately 35–40 cal/kg/day. Overweight sed- entary patients need 20–25 cal/kg/day and active obese patients need 30–35 cal/kg/day, while underweight patients need 35 cal/kg/day if sedentary and 40–50 cal/kg/day if active. In elderly sedentary diabetic patients, 20 cal/kg/day are usually required (after 50 years of age approximately 10% less calories for each decade is required). A more accurate assessment of the caloric needs may be achieved by using appropriate formulas to calculate the rest metabolic rate (RMR), such as those of Harris & Benedict which are based on weight, height, age and sex. Since subjects of the same weight but of different height have similar RMR, formulas may be simplified by considering only weight, age and sex. RMR should be increased by 30, 50 or 70% for low, medium or high levels of physical activity. Table 2 shows the caloric requirement according sex and age for selected weights and activity levels, based on similar formulas. In diabetic children the caloric needs depend on the rate of growth and activity pattern. Children 4–6 years old require 90 cal/kg/day and children 7–10 years old require 80 cal/kg/day. It is important to allow an adequate caloric intake in juvenile diabetes. Caloric requirement in children may also be calculated by adding to the baseline value of 1,000 cal/day the amount of 100–125 cal for every year of age up to 12 years. Youngsters should consume 3 meals daily with 2 or 3 snacks (eaten at the same time each day) to minimize glycemic fluctuations and the risk of hypoglycemic episodes. After the caloric content and the composition of the diet are established, the prescription of a diet was in the past made by utilizing the data in the Exchange Lists for Meal Planning published by the American Diabetes Association. A more useful approach might be to use the precalculated diets (of various caloric content) prepared by several diabetes associations or other authoritative sources. How- ever, it is now recognized that the diet should be individualized and prepared by taking into account the eating habits and other lifestyle factors. It is clinically relevant that 7–35% of adolescent females with type 1 diabetes may have an eating disorder, such as anorexia or bulima nervosa. Dietary Components Dietary Carbohydrate Carbohydrates are the most important source of energy and provide about 4 cal/g. The carbohydrate intake of diabetic patients should be equal to that of nondiabetic subjects. A dietary carbohydrate content of about 50–60% of total energy intake seems adequate in diabetic patients. 59Diet and Modification of Nutrient Absorption Table 2. Caloric needs according to age, sex, weight 1 and physical activity Sex and Weight Physical activity age group kg rest rest low low medium medium high high kcal/kg kcal/day kcal/kg kcal/day kcal/kg kcal/day kcal/kg kcal/day Men 18–30 years old 68 25 1,723 33 2,240 38 2,585 43 2,929 72 25 1,784 32 2,319 37 2,675 42 3,032 76 24 1,844 32 2,397 36 2,766 41 3,135 80 24 1,905 31 2,476 36 2,857 40 3,238 Average 74 24.5 1,814 31.9 2,358 36.8 2,721 41.7 3,084 31–60 years old 68 25 1,667 32 2,167 37 2,500 42 2,833 72 24 1,713 31 2,227 36 2,570 40 2,912 76 23 1,760 30 2,288 35 2,639 39 2,991 80 23 1,806 29 2,348 34 2,709 38 3,070 Average 74 23.5 1,736 30.6 2,257 35.3 2,605 40.0 2,952 Women 18–30 years old 56 24 1,323 31 1,720 35 1,985 40 2,249 60 23 1,383 30 1,798 35 2,074 39 2,351 64 23 1,442 29 1,875 34 2,164 38 2,452 68 22 1,502 29 1,953 33 2,253 38 2,553 Average 62 22.8 1,413 29.7 1,836 34.2 2,119 38.8 2,401 31–60 years old 56 23 1,309 30 1,701 35 1,963 40 2,225 60 22 1,342 29 1,744 34 2,012 38 2,281 64 21 1,374 28 1,787 32 2,062 37 2,336 68 21 1,407 27 1,829 31 2,111 35 2,392 Average 62 22.0 1,358 28.6 1,765 33.0 2,037 37.4 2,309 1 Caloric needs at rest (RMR) per day were calculated according to the following formulas (as reported by G. Bray): for 18- to 30-year-old men: (0.0630¶kg weight+2.8957)¶240; for 31- to 60-year-old men: (0.0484¶kg weight+3.6534)¶240; for 18- to 30-year-old women: (0.0621¶kg weight+2.0357)¶240; for 31- to 60-year-old women: (0.0342¶kg weight+3.5377)¶240. RMR was then multiplied by 1.3, 1.5 or 1.7 for low, medium or high physical activity, respectively. Carbohydrates are available as complex or simple sugars. In diabetic patients, complex carbohydrates or polysaccharides should be preferred. Com- plex carbohydrates include: starches (present in large amounts in rice, cereals, potatoes, pulses and vegetable roots), dextrins (derived from hydrolyzed starch), glycogen (contained in liver and muscle), cellulose or pectins (indigest- 60Iannello Table 3. Glycemic index of some foods Bread 100% Beans 65% Rice 83% Grapes 62% Potatoes 81% Apples 53% Bananas 79% Milk 49% Spaghetti 66% Pears 47% Oranges 66% Lentils 43% ible complex carbohydrates contained in plant foods). In diabetics, simple carbohydrates should be restricted. They include monosaccharides (glucose present in oranges and carrots, fructose present in honey and ripe fruits, and galactose derived from hydrolyzed lactose) and disaccharides (sucrose present in beetroot and sugar cane, lactose present in milk, and maltose derived from hydrolyzed starch). The formerly claimed diabetogenic effect of sucrose overconsumption has not been confirmed by epidemiological or experimental studies. However, in diabetic patients, sucrose-rich foods cause a rapid rise in glycemic values, which can be prevented by consuming these foods as part of a mixed meal. The recommended disaccharide (sucrose plus other glucose- containing disaccharides) consumption by diabetic people should not exceed 5–10% of the total caloric intake. Sucrose addition as sweetener should not exceed 20 g/day. Fructose is a natural monosaccharide, used as a sweetener. It is converted to glucose (and stored as glycogen) or triglyceride in liver. In diabetics with insulin deficiency and impaired hepatic glycogen synthesis, fructose-derived glucose contributes to the hyperglycemia. Thus, the safety of fructose use in diabetes is a debated topic. Starches are hydrolyzed to dextrins, then to maltose and finally to glucose (through the effect of gastric acid and intestinal enzymes). They are useful in the diabetic diet because they are slowly digested and absorbed, inducing lower increments of the glycemic and insulinemic values than equivalent amounts of glucose or simple sugars. It is well established that equimolar amounts of carbohydrate in different foods induce different glycemic postprandial excursions. Jenkins et al. [1981] have elaborated a ‘glycemic index’, representing the incremental area under 2 h glycemic curve of food divided by the corresponding area under 2 h glycemic curve after ingestion of a portion of white bread containing equivalent amounts of carbohydrates, multiplied by 100 (table 3). Reference can also be made to the glycemic response after glucose ingestion, in which instance the glycemic index for glucose is 100. Foods containing simple sugars have a high glycemic index, raising glycemia and insulinemia faster and to a greater extent, and therefore are contraindicated in diabetic patients. However, several factors can influence the food glycemic response, including: (a) type of diabetes, age, 61Diet and Modification of Nutrient Absorption sex, body weight, physical activity and race; (b) physical form of starches, size of food particles, food processing and preparation, fiber or fat or protein content of food, different digestion or absorption or transit of different starch- or sugar-containing foods, etc. Dietary Fat Fats are an important source of energy, providing about 9 cal/g, and difference in the amount and type of dietary fat can have relevant metabolic effects. In patients with IGT or type 2 diabetes or decompensated type 1 diabetes, elevated plasma levels of triglycerides and cholesterol frequently occur. Both hypertriglyceridemia and hypercholesterolemia respond in part to diet alterations. The recommended fat intake is O30% of total calories (=10% of saturated fats, 6–8% of polyunsaturated fats and 14–12% of mono- unsaturated fats given as olive oil). Low-fat diets are often high in carbohy- drate (being the proportion of proteins relatively constant), which may favor hypertriglyceridemia. This effect may be attenuated by supplementation with fibers. Saturated fats (which are solid at room temperature) are most often from animal source (milk, butter, cheese, bacon fat, fatty meat, etc.), but they are also contained in high concentrations in coconut and palm oils. Diets high in saturated fat are atherogenic (increasing total and LDL cholesterol levels) and favor insulin resistance; thus, a diet restricted in saturated fats is recommended. Unsaturated fats (which are liquid at room temperature) derive from vegetable source and include monounsaturated and polyunsaturated fats. A diet high in monounsaturated fatty acids or MUFA (most often assumed as olive oil, as it occurs with the Mediterranean diet) does not increase LDL levels, may improve insulin sensitivity, glycemic control and HDL cholesterol levels, and decreases plasma triglycerides. For this reason, the American Diabetes Associ- ation (ADA) and the European Association for the Study of Diabetes (EASD) set free the intake of monounsaturated fat in diabetic patients. On the contrary, a diet high in polyunsaturated fatty acids or PUFA (such as corn, sunflower and safflower oils) reduces total and LDL cholesterol but decreases HDL cholesterol as well; moreover, some data from the literature would suggest that they may promote carcinogenesis in experimental animals. The intake of cholesterol should be restricted to =300 mg daily, avoiding cholesterol-rich foods (table 4), which can produce a 15–20% reduction of plasma cholesterol level. Excessive cholesterol intake causes increase in total plasma cholesterol and LDL cholesterol, which can be reduced by increasing the polyunsaturated/saturated fat ratio (which should be kept at ?0.8). The polyunsaturated fatty acids of the omega-3 class (eicosapentaenoic and docosahexaenoic acids), which can be formed from -linolenic acid 62Iannello Table 4. Cholesterol content of some foods (mg/100 g) Brain 2,000 Oysters 200 Egg yolk 1,480 Lobster 150 Lamb kidney 804 Cream 133 Chicken liver 746 Cheese, cheddar 100 Caviar 350 Whole milk 34 Butter 250 Egg white 0 (through elongation and desaturation), are contained in fish oils and are useful to reduce the coronary risk of diabetic patients (decreasing VLDL production, lowering arterial blood pressure, reducing platelet aggregation and prolonging bleeding time). This explains the low prevalence of coronary heart disease in the Greenland Eskimos (consuming 5–10 g of fish oil fatty acids daily for a lifetime) and in the Japanese fish eaters of coastal villages. A dietary supplemen- tation with fish or fish oil should, therefore, be recommended. It would be advisable to replace in 2–3 meals a week the red meat with fish. However, three considerations speak against an excessive intake of fish or fish oil: (a) fishes of coastal waters and lakes accumulate a large quantity of mercury and chlori- nated hydrocarbons; (b) in some type 2 diabetic patients, 3-omega fatty acids may deteriorate glycemia (both increasing hepatic glucose production and impairing insulin secretion), and (c) in patients with hypercholesterolemia but without hypertriglyceridemia the metabolic effects of fish oil are uncertain. Recently, new fat substitutes were proposed for use in the diet of diabetic patients. One of these products is named Olestra and is made from sucrose and long-chain fatty acids, is heat-stable, tastes like vegetable oil, promotes cholesterol excretion and is calorie-free being not metabolized or absorbed. Another fat substitute is named Simpless and is made from egg white or whey protein of milk (using a process of microparticulation which confers a taste of fat), has a low-calorie content, and is useful to make ice-cream, yogurt, margarine, cheeses, etc. Dietary Protein Proteins are formed by amino acids and provide about 4 cal/g of energy. Some amino acids cannot be synthesized by humans and must be introduced with diet (essential amino acids). The animal proteins (contained in meat, chicken, fish, egg, milk, etc.) are of high biological value, containing adequate amount of essential amino acids, while vegetable proteins (peas, beans, dry fruits, cereals, etc.) are of low biological value, laking some essential amino acids. Leucine and arginine have important biologic effects, stimulating insulin 63Diet and Modification of Nutrient Absorption [...]... (b) The intermediate-acting insulins comprise the lente insulin, which is a 30 :70% mixture of semilente and ultralente (see later) insulin as well as the Insulin Treatment in Type 1 and Type 2 Diabetes 73 Neutral Protamine Hagedorn (NPH) insulin, obtained by adding the protein protamine to insulin and adjusting the pH (c) The long-acting insulin preparations include the ultralente insulin, obtained by... recombinant DNA technique is used Duration of Action: Three types of insulin are available which differ in the duration of action: (a) the rapid-acting, (b) the intermediate-acting and (c) the long-acting insulin (a) The rapid-acting insulin preparations include the regular insulin as well as the semilente insulin which is a suspension of insulin and zinc in acetate buffer (with formation of zinc-insulin... insulin contains threonine, isoleucine and threonine at the same sites Porcine insulin is more similar to human insulin inasmuch as it has the same amino acids as bovine insulin at positions A-8 and B -3 0 but the same amino acid as human insulin at position A-10 Human insulin can be obtained by modification of animal (pork) insulin (human semisynthetic insulin) or can be synthesized by the recombinant DNA... Thus, rapid-acting insulin, beginning to act in about 30 min, should be given 20 30 min (perhaps 45 min) before a meal to optimize synchronization of postprandial glycemia and circulating insulin levels It is effective in blunting elevations in glucose following meals and for rapid adjustments in insulin dosage, but the pharmacokinetics of rapid-acting insulins entails that a definite time interval is... titers of insulin antibodies and therefore is most useful in patients who are initiating insulin therapy (and who have not yet produced antibodies) and in patients requiring insulin intermittently (intermittent use of insulin increases its antigenic effects) Destruction of Insulin Insulin is destroyed variably at the site of injection by some insulindegrading enzymes An unusual cause of altered insulin pharmacokinetics... Therefore, during insulin treatment, liver is relatively hypoinsulinized and the peripheral tissues relatively hyperinsulinized Depth of Injection and Massage The depth of insulin injection is an important variable In fact, the deeper insulin is injected, the quicker the onset of action and the higher the peak Insulin Treatment in Type 1 and Type 2 Diabetes 77 Usually, it is recommended to place insulin consistently... modifying, during the preparation, the pH of a mixture of zinc and insulin to produce larger zinc-insulin crystals (the larger the crystals, the slower the release of the injected insulin) as well as the protamine-zinc insulin obtained by adding also protamine and adjusting the pH After subcutaneous injection, regular insulin presents a rapid onset of action (0.5–1 h), an early peak of activity (2–4 h) and. .. injected in that extremity; moreover, stress (by increasing epinephrine) may affect local blood flow and absorption of insulin Insulin Antibodies Insulin antibodies bind insulin and can delay the onset of action and the duration of its effect Among patients, the time course of a given insulin preparation is highly variable, probably for differences in circulating insulin antibodies Human insulin generates... between insulin injection and eating A better synchrony between insulin peaks and meal absorption after injection of rapid-acting insulin is observed with human insulin, which acts more rapidly after injection and exerts shorter effects compared to previously used animal insulins Intermediate-acting NPH insulin presents a delayed onset of action (3 4 h), a delayed peak of activity (8–12 h) and a duration... lente insulin The NPH and lente intermediate-acting insulins have the same, long time-course of action, which is useful to provide the basal level of insulin through the 24 h when given twice per day Intermediate-acting human insulin produces earlier peaks, that may cause hypoglycemic events during sleep and fails to maintain an adequate effect for a full 24-hour period Ultralente (long-acting) insulins . 2,709 38 3, 070 Average 74 23. 5 1, 736 30 .6 2,257 35 .3 2,605 40.0 2,952 Women 18 30 years old 56 24 1 ,32 3 31 1,720 35 1,985 40 2,249 60 23 1 ,38 3 30 1,798 35 2,074 39 2 ,35 1 64 23 1,442 29 1,875 34 . 1,814 31 .9 2 ,35 8 36 .8 2,721 41.7 3, 084 31 –60 years old 68 25 1,667 32 2,167 37 2,500 42 2, 833 72 24 1,7 13 31 2,227 36 2,570 40 2,912 76 23 1,760 30 2,288 35 2, 639 39 2,991 80 23 1,806 29 2 ,34 8 34 . kcal/day Men 18 30 years old 68 25 1,7 23 33 2,240 38 2,585 43 2,929 72 25 1,784 32 2 ,31 9 37 2,675 42 3, 032 76 24 1,844 32 2 ,39 7 36 2,766 41 3, 135 80 24 1,905 31 2,476 36 2,857 40 3, 238 Average 74