secretion (throughout the day and night) and acute increases of insulin levels connected to ingestion of meals. This regimen improves diabetic control, re- duces excursions in glycemic levels and provides a good flexibility. Four differ- ent regimens may be used: (a) The simplest intensive regimen entails the use of three injections, regular and intermediate-acting insulin before breakfast, regular insulin before supper and intermediate-acting insulin at bedtime. This 3 times daily insulin dose regimen is useful in diabetic patients with frequent nocturnal hypoglyce- mia and pre-breakfast hyperglycemia. The primary disadvantage of this approach is that meal schedules must be fixed rather rigidly. (b) Regular insulin before each meal and intermediate-acting insulin at bedtime (4 daily insulin doses). This regimen provides the greatest flexibility because regular insulin can be adjusted to cover each meal, avoiding postpran- dial hyperglycemia. (c) Regular and intermediate-acting insulin before breakfast, regular insu- lin before lunch and supper, and intermediate-acting insulin at bedtime (4 daily insulin doses). (d) Regular insulin before each meal and ultralente insulin in the morning (to replace basal insulin secretion) or subdivided before breakfast and before supper (4 daily insulin doses). It is less preferable to the (b) regimen because ultralente presents unexpected small peaks 15–24 h after injection. Human insulin lispro is very appropriate for multiple injection therapy, especially in patients with marked postprandial hyperglycemia and nocturnal hypoglycemia or with a variable lifestyle. Patients on insulin lispro had significantly lower glucose levels following meals (however with the potentially unwanted result of a rise in preprandial glucose) and showed a reduction in the incidence of severe hypoglycemia by 30% (compared to regular human insulin). In patients treated with insulin lispro (compared to those treated with human regular insulin) there should be less need for snacks. The majority of patients on insulin lispro reported an improved quality of life. However, there are some ‘failures’ with this type of insulin, as a number of patients may appear unable to control their diabetes with insulin lispro. At present, insulin lispro should be used with caution in children under the age of 12 as well as in gestational diabetes or pregnancy, because of lack of experience. Other, far too complex, multiple-injection regimens have also been sug- gested. Certainly, the adherence to therapy is less likely to occur when the program of treatment is far too complicated. Some patients object to such frequent needle injections and ask for changing from this insulin regimen to a simpler program. Pen devices or jet injectors filled with insulin (that are easy to carry) make the multiple daily insulin regimens better accepted. 81Insulin Treatment in Type 1 and Type 2 Diabetes It is advisable to use no more than two types of insulin. It is noteworthy that in some patients a morning fasting hyperglycemia (the dawn phenom- enon) occurs, that depends on the hepatic glucose overproduction activated in the morning due to inadequate overnight delivery of insulin and a sleep- associated GH release. This phenomenon is most pronounced in type 1 diabetic patients for their inability to compensate by raising endogenous insulin secretion. The magnitude of the dawn phenomenon can be attenuated by designing insulin regimens which ensure that the effects of exogenous insulin do not peak in the middle of the night and then become dissipated by morning. Some patients (about 1/3 of type 1 diabetic patients) may experience early in the course of disease a brief honeymoon period, during which there is a partial recovery of -cell function and a transient or a prolonged fall in the exogenous insulin requirement (=0.5 U/kg/day). The honeymoon phenom- enon may be due to the termination of a ‘stress’ episode (infections, etc.) that has anticipated the manifestation of diabetes in a subject with ongoing -cell destruction process. Spontaneous remission is less frequent in children and adolescent or pubertal patients, and more frequent in adult postpubertal pa- tients. A low residual insulin secretion (probably linked to a more aggressive destruction of -cells) can be implicated in children while a low insulin sensitiv- ity (probably linked to the increased secretion of GH hormone) may be impor- tant in pubertal patients. The honeymoon should not be regarded as a signal to reduce efforts aimed at glycemic control, because optimized insulin therapy may help to preserve -cell function. It is recommended to continue insulin treatment even at low doses (even 1–4 U/day), since this can preserve -cell function and may favor the remission. Continuous Subcutaneous Insulin Infusion (CSII) In sufficiently motivated diabetic patients, an alternative that provides a greater flexibility of insulin treatment (minimizing variations in its absorp- tion) is CSII, with which insulin delivery may somewhat mimic that occurring in nondiabetic individuals. Insulin delivery pumps may be implantable or portable (with ‘closed loop’ or ‘open loop’ insulin infusion systems). The CSII method administers rapid-acting insulin around the clock using a battery-powered (externally worn) infusion pump, that delivers basal rates continuously (usually 0.5–2.0 U/h) and can be programmed to vary the flow rate automatically, reducing the flow rate at 1.0–4.0 a.m. and increasing it to compensate for increased insulin requirements early in the morning. Before meals, insulin boluses are given by manually activating the pump, in amounts based on frequent blood glucose self-monitoring determinations. Usually, a 3- to 5-day hospital stay is required for learning to use the insulin pump, 82Belfiore/Iannello Table 3. Problems limiting the use of CSII Interruption of insulin delivery (commonly due to insulin precipitation within the catheter) that leads to rapid severe hyperglycemia and ketoacidosis (because there is no depot insulin and all insulin being used is short-acting) Pump malfunction (a pump malfunction with insulin overdose can produce severe and even fatal hypoglycemia) Loss of battery charge Leakage from the catheter Empty insulin reservoir Needle displacement Local infections (such as abscesses at the catheter site, only occasionally reported) and successively a health-care professional should be available 24 h/day to assist the patient. Most pumps contain a syringe or a reservoir filled with insulin attached to an infusion set consisting of a catheter and a 27-gauge needle which is inserted into subcutaneous tissue (preferably in the abdomen). Unfortunately, the CSII presents several problems that limit its use (table 3), and the patients with brittle diabetes (see below) may not be the best candidates for a successful use of CSII. Most modern pumps present alarm systems for the different pump problems. Some diabetic patients are absolutely incapable to safely employ the insulin pump and to use the appropriate infusion rates. The high cost is another relevant disadvantage of CSII. Self-Monitoring Self-monitoring is an important component of diabetes management, which helps to achieve a good glycemic control and therefore to prevent complications (especially microangiopathy). Several factors may influence the method and frequency of self-monitoring, such as the type of insulin regimen prescribed, glycemic goals of therapy, capabilities of diabetic patient, etc. Self- monitoring includes the following tests: (a) Urine testing for glucose (2 or 4 times/day) is the less reliable option for self-monitoring, inasmuch as it allows only a coarse estimation of glycemia. It might be used for insulin or dietary adjustments in patients with stable diabetes. (b) Urine testing for ketones is a component of self-monitoring routines of type 1 diabetic patients, especially in presence of unexplained hyperglycemia or to manage acute events of metabolic decompensation. 83Insulin Treatment in Type 1 and Type 2 Diabetes (c) Blood glucose self-monitoring is the most important advance in dia- betes care. It requires the use of devices or meters that read blood glucose testing strips. All the modern meters can store and recall obtained blood glucose readings. These glucose determinations provide an estimation of gly- cemic control at any given moment, from day to day, and may be especially useful for specific problems (hypoglycemia, acute illness, ketonuria, periods of unstable diabetes, etc.). Several factors may limit the use of this method, such as a low level of motivation, a poor accuracy of determination, technical errors, intellectual inability to use the glycemic results, low visual or physical abilities, lack of education, high costs, etc. For some diabetic patients, blood glucose self-monitoring is perceived as too difficult or intrusive into individual’s routine, while other patients who desire to improve their glycemic control may accept to perform blood glucose tests several times a day on a regular basis. In these motivated patients, it is very important to monitor their technical competence, to define the desired glycemic range to be achieved, and to provide all the appropriate technical instructions, including the comparison of meter- obtained results with laboratory values. Glycated Hemoglobin (HbA 1c ) The patient with diabetes should have a periodic determination of HbA 1c because this measurement is the most objective method of glucose control measurement over a long period. HbA is glycated in an irreversible and non- enzymatic fashion, and the levels of HBA 1c reflect the mean glycemia over the 2–3 months prior to the test. Serum Fructosamine Test This test has been suggested as a less difficult to perform and less costly alternative to HBA 1c determination, with which shows a good correlation. This test measures the level of glycosylated proteins in the blood (mainly albumin), and reflects the mean glycemic control during a 2- to 3-week period. Its validity is uncertain when interfering substances (bilirubin, hemolysis, etc.) are present or serum albumin concentration is abnormal. The test accuracy can be improved by correcting the fructosamine result for variations in serum albumin. HBA 1c , compared to fructosamine test, should be considered as the preferable test for monitoring diabetic control. 84Belfiore/Iannello Complications of Insulin Treatment The most important complication of insulin therapy is hypoglycemia, which is discussed in chapter VIII (Clinical Emergencies in Diabetes. 2: Hy- poglycemia). The other complications are listed below. Insulin Edema In poorly controlled diabetic patients, insulin therapy can result in a marked accumulation of fluid, with localized (periorbital, pretibial or presa- cral) or generalized edema. The causes are probably multiple (table 4). A dietary restriction of salt and a temporary use of diuretics can be recom- mended. Edema will most often subside within 3–5 days. Table 4. Causes of insulin edema ADH increase (ascribed to hypovolemia resulting from osmotic diuresis) Cessation of natriuretic effect of hyperglucagonemia Increased plasma volume and transcapillary escape of albumin (with reduced colloid osmotic pressure) Excessive infusion of isotonic saline Na retention (induced by excess of insulin infused or injected) Insulin Lipoatrophy It was a common complication prior to the introduction of monocompo- nent insulins, consisting of a loss of fat at the site of insulin injection or, occasionally, at distant sites. In 25% of lipoatrophic patients, local allergy coexists. Lipoatrophy is frequently observed in young children (50%) or in young women (20%), compared to male adults (5%). Lipoatrophy, moreover, may occur after repeated injections of other substances such as narcotics or GH preparations. Thus, atrophy might be the result of a repeated mechanical trauma, even if insulin impurities can stimulate immune factors or immune complex formation which lead to local release of lipolytic substances. These reactions occur without overt inflammation and were considered also second- ary to insulin degradation or aggregation products. Indeed,inbiopsyspecimens of lipoatrophic areas, antigen-antibody reactions were not seen. Local reactions to protamine (a constituent of insulin preparations) and to silicone oil (the lubrificant in disposable syringes) may play a role in some patients. Switching to purified or human insulins and rotating the site of injections result in improvement of skin alterations in 97% of lipoatrophic patients. Very few cases were reported with recombinant human insulins, and the reason why it 85Insulin Treatment in Type 1 and Type 2 Diabetes still occasionally occurs is unknown. Injecting the purified insulin at the edges and center of the affected atrophic area improves lipoatrophy (due to the lipogenic effect of insulin). Addition of dexamethasone to the insulin in the syringe (4 g/U, total daily dose not exceeding 0.75 mg) has also been sug- gested. In a recent case of severe well-circumscribed lipoatrophy, good results were obtained by treating the area with a fatty acid mixture while the patient was instructed to avoid this area for insulin injection. Insulin Lipohypertrophy It consists of visible or palpable increase of localized subcutaneous fat (most prevailingly in the anterior or lateral part of thighs) at the site of insulin injection, sometimes coexisting with lipoatrophy. Repeated and prolonged use of the same site for insulin injection is a main determinant in the development of lipohypertrophy. Often the affected patients report that injection into lipohy- pertrophic areas is less painful, perhaps because the subcutaneous tissue tends to be fibrous. Lipohypertrophy is due to a possible growth factor effect of insulin on cellular elements of subcutaneous tissue, and may alter the absorp- tion rate of insulin, thus possibly affecting metabolic control. Prevalence rates of lipohypertrophy vary between 20–45% in type 1 and 3–6% in type 2 diabetic patients. Independent risk factors which contribute to the presence of lipohy- pertrophy are female sex, type 1 diabetes, higher BMI and missing rotation of insulin injections. The most severe cases of insulin lipohypertrophy can be treated with liposuction, but prevention is important, primarily by systemat- ized rotation of injection sites within the recommended areas. An important role is played by educational interventions to establish an organized rotation system for insulin injection sites, to self-recognize lipohypertrophy and to normalize the high BMI. Syndrome of Immunologic Insulin Resistance All patients who receive insulin develop circulating antibodies, whose production can be influenced by several factors (table 5). Patients never treated with exogenous insulin may have circulating insulin antibodies, probably in- volved in the autoimmune reactions of type 1 diabetes. The high level of insulin antibodies may function as a reservoir from which insulin may be released unpredictably (thus inducing delayed hypoglycemia), or may bind insulin (thus causing hyperglycemia), or may form immune complexes (thus sequestering insulin in the reticuloendothelial system or stimulating procoagulant activity and favoring diabetic complications). In diabetic patients, this syndrome may result in an excessive insulin requirement (100–200 U/day in adults and up to 2.5 U/kg in children). In the most severe cases, steroids even at high doses for 3–4 weeks should be used. It is noteworthy that the immunogenicity of insulin 86Belfiore/Iannello Table 5. Factors influencing the formation of insulin antibodies Insulin species (human insulin is less immunogenic than animal insulins) Insulin purity (monocomponent insulins are less immunogenic) Insulin pharmaceutical form (regular insulin is less immunogenic than modified insulins) Pattern of insulin treatment (episodic therapy and CSII may increase insulin immunogenicity) Genetic factors (HLA-A2-B44 and HLA-B44-DR7 predispose to immune complications of insulin therapy) Residual insulin secretion (when present, it reduces immune response to insulin) lispro has been found to be similar to that of human insulin in both type 1 and type 2 diabetic patients. Insulin Allergy It includes different forms: (a) Local allergycomprisesimmediate orbiphasicordelayedreactionsand consists of erythematous and pruritic indurated lesions or more severe reactions in subcutaneousareasinjectedwith insulin preparations. Protamineorzinc have beenimplicated. ThesereactionsareIgE-dependentandmayoccurwithconven- tional insulin treatment or CSII in subjects with intermittent insulin treatment or with allergy to other drugs (such as penicillin) or with obesity. The affected patients will improve within 30–60 days continuing the use of insulin (probably because ofaspontaneous desensitization),whereasinthe mostseverecaseslocal steroids in low doses or oral antihistaminics may be considered. (b) Generalized allergy ranges from a simple urticaria to more severe reactions such as anaphylaxis with angioedema, bronchospasm, pharyngeal edema and collapse. These generalized reactions are due to the interaction of insulin (acting as an antigen) with specific IgE bound to mast cells or blood basophils and are very uncommon (=0.05%). No deaths for insulin allergy are reported. Human insulins are efficacious in the majority of allergic patients for the treatment of this systemic allergy, while in the remainder desensitization is successful (about half of patients who cannot be desensitized are overweight). Immunologic insulin resistance may coexist with or following insulin allergy. Insulin allergy is different from stress-induced urticaria, in which the central nervous system is important in the generation of immune response. Conditions of Altered Insulin Responses Conditions of altered insulin responses include: (a) insulin resistance linked to occult infections; (b) iatrogenic hypoglycemia or factitious inten- 87Insulin Treatment in Type 1 and Type 2 Diabetes tional insulin overdosing (see chapter VIII on Clinical Emergencies in Dia- betes. 2: Hypoglycemia); (c) labile or ‘brittle’ diabetes, which can be idiopathic or secondary and includes a group of insulin-dependent diabetic patients (about 2–10%) characterized by unexplainable and extreme glycemic short- term and long-term fluctuations with frequent ketosis proneness or hypogly- cemic crises, or both. Brittle diabetes can depend on altered insulin absorp- tion, or poor residual insulin secretion, or excess of counter-hormone regulation, or emotional stress. Some of these patients are adolescent women who distort their insulin treatment to prolong the stay in the hospital for psychosocial problems. In these instances, the treatment of brittle diabetes requires a strong effort by the patient’s family and the medical and psycholog- ical team. Role of Education A successful insulin management requires actively applied systems of patient education. The aim of education and training is to provide adequate information in a simple form suitable to the ability of the subject, in order to allow the diabetic patients to develop the required knowledge to self-manage their disease and to ensure an optimal and appropriate use of insulin therapy (and other therapeutical measures). Behavioral changes and insulin treatment adjustments may be made in a graduated manner (step-by-step), and a system- atic reinforcement is critical after the goals are achieved. Nutritional manage- ment is also an integral part of initial and following programs of education. The provision of a diabetes professional team (doctors, educators or diabetes nurse specialists, nutritionists or dieticians, and podiatrists or chiropodists) is also necessary as well as a continuing education for the professional staff. Several factors should be considered for a good therapy, including patient’s lifestyle, physical activity, dietary habits, glucose self-monitoring, correct time to injection (some patients may take regular insulin 5–15 min before the meal, instead of 30 min before), insulin dosage adjustments, usual injection sites and, finally, possible interactions with otherdrugs. How to avoid hypoglycemia, what to do during an episode of hypoglycemia or the correct behavior during acute illness or stress must be included in the education program. Each visit should be an opportunity to assess the current level of self-management, the behavioral change and goal achievement. Overall glycemic control is optimized when education and motivation are emphasized. In this approach, every dia- betic patient should be considered unique. 88Belfiore/Iannello Suggested Reading Anderson JH, Brunelle R, Koivisto VA: Reduction of post-prandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin analog treatment. Diabetes 1997;46:265–270. Campbell PJ, May ME: A practical guide to intensive insulin therapy. Am J Med Sci 1995;310:24–30. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986. Dimitriadis G, Gerich J: Importance of timing of preprandial subcutaneous insulin administration in the management of diabetes mellitus. Diabetes Care 1983;6:374–377. Galloway JA, deShazo RD: Insulin chemistry and pharmacology; insulin allergy, resistance, and lipodys- trophy; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. Amsterdam, Elsevier, 1990, pp 497–512. Sane T, Helve E, Yki-Jarvinen H: One year’s response to evening insulin therapy in non-insulin-dependent diabetes. J Intern Med 1992;231:253–260. Strowing S, Raskin P: Insulin treatment and patient management; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. Amsterdam, Elsevier, 1990, pp 514–525. 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 89Insulin Treatment in Type 1 and Type 2 Diabetes Chapter VI Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 90–102 Overview of Diabetes Management: ‘Combined’ Treatment and Therapeutic Additions F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy Lessons from Recent Large Trials on Diabetes Treatment The Diabetes Control and Complication Trial (DCCT), a large multicenter study conducted on more than 1,400 type 1 diabetics (aged 12–39 years) for a period of 7–10 years, has established that close blood glucose control (even if complete normalization of glycemic level was not obtained) reduces the frequency of late diabetic complications. Patients were assigned randomly to either intensive insulin therapy (3 or more daily injections or insulin pump, glucose self-monitoring 4 or more times per day, and frequent contact with a diabetes health-care team) or conventional therapy (1 or 2 injections of insulin mixtures per day, less frequent monitoring and medical contacts). The target goals of therapy were markedly different. Compared to the conventional care group, the intensive care group showed lower glycated hemoglobin (by 1.5–2.0%) and mean glucose level (by 60–80 mg/dl), yet most of the intensive care patients group failed to achieve normal glycemic levels. However, intensive care reduced the development of retinopathy by 76% (and its progression by 54%), the risk of microalbuminuria by 39%, frank proteinuria by 54%, and clinical neuropathy by 60%. Major cardiovascular events were also reduced, although statistical significance was not reached, in any case excluding that intensive insulin therapy may entail risk for macrovascular complications. The correlation of mean blood glucose with the frequency of retinopathy progression was linear, suggesting that there is no threshold glycemic level at which complications occur, so that any degree of improvement in glycemic control exerts beneficial effects on the progression of complications. These 90 [...]... IL-10 and TNFAnticytokine and anti-IFN- antibodies Anti T-cell antibodies, anti-CD3, -CD4, -CD8 Anti T-cell-receptor antibodies Anti-MHC class I and class II antibodies Immunosuppressive drugs (cyclosporine) Immunomodulating agents Adjuvants (BCG vaccine and CFA) Nicotinamide Treatment with autoantigen: Insulin GAD Heat-shock protein Table 3 Immunoregulation treatments in diabetic humans Cyclosporine treatment. .. since no study has yet demonstrated its potential benefit on the complications and long-term prognosis of diabetic patients Insulin-Like Growth Factor I (IGF-I ) IGF-I (or somatomedin C) is one of the major components of nonsuppressible insulin-like activity IGF-I and insulin share common steps in signal transduction, and the action of IGF-I on carbohydrate metabolism is preserved in certain insulin-resistant... Management 99 Table 4 Effects of acarbose treatment Delay in digestion of complex carbohydrates Reduction in glucose absorption Decrease in postprandial glycemia Decrease in postprandial insulinemia Decrease in postprandial C-peptide level Decrease in fasting glycemia (only in some diabetic patients) Increase in breath hydrogen Decrease in nutrient-stimulated insulin secretion Decrease in nutrient-stimulated... feeding with insulin (which is a -autoantigen in susceptible subjects), and nasal immunization or oral feeding with GAD, IA-2, ICAp69 and heat-shock protein Gene Therapy It is the frontier of immunological therapy in diabetes mellitus and is directed to express regulatory cytokines (such as IL -4 , IL-10 and TGF- ) or autoantigens in the thymus (selection of T cells in the thymus results in deletion of... DE, Flier JS: Insulin-like growth factor I as a therapeutic agent for hyperinsulinemic insulin-resistant diabetes mellitus Diabetes Res Clin Pract 1995;28(suppl): 185–1 94 Singh B: Possible immunological treatment for type 1 diabetes in the 21st century Pract Diabetes 1997; 14: 197–200 Thomson RG, Pearson L, Schoenfeld SL, Kolterman OG, and the Pramlintide in Type 2 Diabetes Group: Pramlintide, a synthetic... 30 40 % of patients require significantly less insulin or sulfonylureas when treated this way These patients, usually, show higher basal and stimulated serum C-peptide levels and increased insulin-mediated glucose disposal The beneficial effects of the combination sulfonylurea-insulin can depend on an increase of endogenous insulin secretion or on a reduction of liver and peripheral insulin resistance, and. .. because of interruption or inadequacy of insulin administration or in the setting of the first manifestation of type 1 diabetes Counterregulatory hormones may increase following physical (infections, surgery, trauma) or emotional stresses, and oppose insulin action In addition, epinephrine may also stimulate glucagon release, which is also favored by lack of insulin The deficiency of insulin reduces... hypersecretion and reduced circulating IGF-I levels are prevalent in poorcontrolled insulin-dependent diabetes Recently, both bacteria and fungi have been engineered to produce sufficient quantities of recombinant human IGF-I (rhIGF-I), so that rhIGF-I has been proposed as a potential therapeutic agent in the treatment of both type 1 and type 2 diabetic patients rhIGF-I not only improves glucose tolerance and increases... Guide to Type 2 (Non-Insulin-Dependent) Diabetes mellitus Brussels, IDF, 1999 Laakso M: Benefits of strict glucose and blood pressure control in type 2 diabetes Lessons from the UK Prospective Diabetes Study Circulation 1999;99 :46 1 46 2 Lebovitz HE: Oral hypoglycemic agents; in Rifkin H, Porte D (eds): Diabetes mellitus Theory and Practice, ed 4 New York, Elsevier, 1990, pp 5 54 5 74 Linse L, Brasseur R,... with -glucosidase inhibitors, and (c) sulfonylureas with PPAR agonists Combined Sulfonylurea-Metformin Therapy The oral hypoglycemic drugs, sulfonylureas and metformin, are largely used in combination in the treatment of type 2 diabetic patients, inasmuch as they exert different and complementary effects Sulfonylureas stimulate insulin secretion whereas metformin ameliorates insulin action by enhancing . (regular insulin is less immunogenic than modified insulins) Pattern of insulin treatment (episodic therapy and CSII may increase insulin immunogenicity) Genetic factors (HLA-A2-B 44 and HLA-B 4 4- DR7. avoiding postpran- dial hyperglycemia. (c) Regular and intermediate-acting insulin before breakfast, regular insu- lin before lunch and supper, and intermediate-acting insulin at bedtime (4 daily. pp 49 7–512. Sane T, Helve E, Yki-Jarvinen H: One year’s response to evening insulin therapy in non-insulin-dependent diabetes. J Intern Med 1992;231:253–260. Strowing S, Raskin P: Insulin treatment