590 Genetics Type 1diabetes The overall lifetime risk in a Caucasian population of developing type 1 dia betes is only 0.4%, but this rises to \200 1 \200\2232% if your mother has it. \200 3 \200\2236% if your father has it. \200 6% if siblings have it. \200 Monozygotic twins h ave a 40% concordance rate. Islet cell antibodies are seen in only 0.3% of the general popu lation but in 40 \200\22350% of monozygotic twins and 5% of siblings of type 1 patients. A genetic predisposition is therefore suggested, but this also highlights the importance of e nvironmental triggers, as not all those with antibodies go on to develop diabetes. Genetic predisposition accounts for 1/3 of suscep- tibility to type 1 diabetes. Although several different regions of the human genome are linked to the development of typ e 1 diabetes, the most common are the major histocompatibility complex (MHC) antigens and h uman leukocyte antigens (HLA). In the United States, more than 90% of patients with type 1 diabe- tes have HLA-DR3, DR4, or both. Certain variants of the DQB1 or DQA1 gene result in expression of susceptible alleles of DR 3/DR4. This association is not true in all races, notably the Japanese. There are currently 10 distinct genetic areas (IDDM1 \200\223IDDM10) known to be linked to type 1 diabetes; some relate to MHC genes, others to the insulin gene region. MHC antigens commonly found in those with type 1 diabetes and felt to predispose to it are B15, B8, and DQ8. The DR2, DQ6, and DQ18 genes appear to be protective. Linkage studies have suggested type 1 susceptibility genes on the fol- lowing chromosomes: \200 6q (also known as IDDM5) \200 11p (IDDM2) \200 11q (IDDM4) \200 15q (IDDM3) These genetic variations may help explain susceptibility, but their link to i levels of islet cell antibodies, antiglutamate decarboxylase (GAD) antibodies, and ant ityrosine phosphatase antibodies (anti-IA-2 antibodies) often seen soon after diagnosis is less clearly decided. If all of these three antibodies are present in a nondiabetic individual, the person has an 88% chance of developing type 1 diabetes within the next 10 years. Maturity-onset diabetes of the young (MODY) The genes known to be involved in MODY are grad ually i as our under- standing of insulin signaling and receptors expands. 103-Draznin-Chap103.indd 590 3/31/2011 4:46:08 PM GENETICS 591 MODY 1 (HNF4A) \200 Accounts for <0.0001% of all type 2 patients and about 5% of cases of MODY Usually presents in adolescence or early adulthood, <25 years of age \200 Can give severe hyperglycemia, with 20% needing insulin therapy and 40% needing oral agents Results in a high frequency of microvascular complications \200 Inherited as an autosomal dominant disorder with a defect on chromosome 20q, resulting in altered activity of the hepatic nuclear factor (HNF)4A gene, w hich is a positive regulator of HNF1A. This is a transcription factor found in the liver an d B cells of the pancreas, where it acts as a transactivator of the insulin gene in rat mod els. MODY 2 (glucokinase) \200 Accounts for <0.2% of type 2 patients and 10 \200\22314% of cas es of MODY \200 Presents in early childhood \200 Gives only mild hyperglycemia and thus infrequent microvascular complications, with 90% of patients being controlled on diet alone and insulin usually only needed when becoming pregnant Autosomally dominantly inherited with a defect in the glucokinase gene on chromosome 7. This results in altered glucose sensing in the B cells of the pancrea s and impaired hepatic production of glycogen. MODY 3 (HNF1A) \200 Affects 1 \200\2232% of type 2 patients and accounts for 70% of MODY patients Presents in adolescence or early adulthood (peaks around 21 years of age) Causes severe hyperglycemia and frequent microvascular complications; 1/3 require insulin therapy and 1/3 require oral agents Linked to a mutation on chromosome 12q24 that directly alters HNF1A activity. How this caus es type 2 diabetes is not fully understood. MODY 4 (IPF-1) \200 Accounts for <1% of cases of MODY \200 A mutation occurs in transcr iption factor gene IPF-1, which in its homozygous form leads to total pancreatic agenesis. MODY 5 (HNF1-B) \200 Accounts for 3% of cases of MODY \200 Average age of presentation is 22 years, with renal cysts (RCAD \200\224renal cysts and diabetes) and often uterine abn ormalities, gout, and insulin resistance Type 2 diabetes In patients with type 2 diabetes, the concordance between monozygotic twins for diabetes is much higher (60 \200\223100% vs. 40% for type 1), but the rate among dizyg otic twins is much less, suggesting a much stronger genetic element in its etiology than fo r type 1 diabetes. Unlike patients 103-Draznin-Chap103.indd 591 3/31/2011 4:46:08 PM CHAPTER 103 Classi \201 cation and diagnosis 592 with type 1 diabetes, however, those with type 2 do not seem to have the same HLA-linked ge nes. In most families this appears to be polygenic, although the much less common MODY is autoso mal dominant but only accounts for a few per- cent of all type 2 patients. MODY is currently split into four types, with type 4 accounting for 15% of cases and for th ose cases that do not \201 t into types 1 \200\2233, although a chromosome 13 defect in t he insulin promoter factor 1 gene may fall into this group. Other recognized genetic subtypes of type 2 diabetes include mitochon- drial diabetes, whic h affects 1 \200\2233% of type 2 patients and is maternally trans- mitted. It is associated with deafness and other neurological abnormalities. Insulin resistance is an important par t of type 2 diabetes, and rare genetic defects causing this are recognized. A 40% reduction in the biological effect of any given insulin molecule is suggested by clamp studies in ty pe 2 patients, but these rarer genetic syndromes may result in a more severe picture. Further reading Alberti KG, Zimmet PZ, for the WHO consultation (1998). De \201 nition, di agnosis and classi \201 cation of DM and its complications. Part 1: Diagnosis and classi \201 cation of DM. Provisional report of a WHO consultation. Diabet Med 15:539 \200\223553. Alcolado JC, Thomas AW (1995). Maternally inherited DM: the role of mitochondrial DNA defec ts. Diabet Med 12(2):102 \200\223108. Hattersley AT (1996). Maturity onset diabetes of the young (MODY). Bailliere Clin Paediatr 4(4):663 \200\223680. Robinson S, Kessling A (1992). Diabetes secondary to genetic disorders. Bailliere Clin Endo crinol Metab 6:867 \200\223898. World Health Organization (1985). Diabetes Mellitus: Report of a WHO Study Group (Technical Report Series no. 727). Geneva: World Health Organization. World Health Organization (1999). De \201 nition, Diagnosis and Classi \201 cation of Dia betes Mellitus and its Complications. Report of a WHO Consultation. Part 1, Diagnosis and C lassi \201 cation of Diabetes Mellitus . Geneva: World Health Organization. 103-Draznin-Chap103.indd 592 3/31/2011 4:46:08 PM BACKGROUND 593 General management and treatment Background After diagnosis, all patients with diabetes need to see a dietitian and have a f ull medical assessment. The \201 rst priority is to decide whether this is a person with type 1 or type 2 diabetes, as the former needs insulin imme- diately whereas the later need s initial dietary advice. Such advice should always take into account the patient \200\231s circumstances and culture and be individually tailored to be achievable. 104-Draznin-Chap104.indd 593 3/31/2011 4:47:45 PM CHAPTER 104 General management and treatment 594 Assessment of the newly diagnosed patient History \200 Duration of symptoms, e.g., thirst , polyuria, weight loss \200 Possible secondary causes of diabetes, e.g., acromegaly \200 Family history \200 Presence of complications of diabetes \200 Risk factors for d eveloping complications, e.g., smoking, hypertension, hyperlipidemia Examination \200 BMI \200 Clues for secondary causes \200 Cardiovascular system \200 \224especially BP + peripheral pulses \200 Signs of autonomic and peripheral neuropathy \200 Eyes \200\224for retinopathy \200 Feet Investigations Initial investigations will be modi \201 ed by the history and examination but as a minimum should include the following: \200 Blood tests for urea and electrolytes , liver and thyroid function, and a full lipid pro \201 le Urine tests for ketones, macro- and (if negative) microalbuminuria \200 An ECG in all pat ients with type 2 diabetes Treatment In patients with type 1 diabetes, insulin therapy is mandatory, along with dietar y advice and standard diabetes education. The education of all newly diagnosed patients is intended to provide an incentive for good compli- ance. A full education package should inc lude the following: \200 An explanation of what diabetes is and what it means to the pati ent \200 Aims of treatment, e.g., rationale of reducing complications and exact values to aim for Types of not just drugs but also dietary advice and lifestyle modi \201 cation, such as i physical activity, stopping smoking, and reducing alcohol inta ke Self-monitoring, the reasons for doing it, and what to do with the results \200 An idea o f some chronic complications of diabetes and what to watch for, e.g., a podiatrist \200\231 s input and review is advised, especially for those with type 2 diabetes. All patients with type 2 diabetes should be considered for such an educational package. In most patients the next step is to try diet, exercise, and weight reduction (if obese, wh ich most will be) before initiating drug therapy if control is not adequate. If this fails to improve control adequately after 1 \200\2232 months, consider oral therapy with metformi n in the overweight and sulfonylureas in the lean if there are no contraindications. 104-Draznin-Chap104.indd 594 3/31/2011 4:47:45 PM ORAL HYPOGLYCEMIC AGENTS 595 After the initial assessment, all patients should be put into a formal review system, wheth er by their PCP or an endocrinologist, for further education, maintenance of good control, and complication screening. Dietary advice In the overweight patient (e.g., BMI >27), a reduction in total calorie inta ke to aid weight reduction is also required. A standard diabetic diet should aim to have th e following: \200 <10% of its energy in the form of saturated fat (<8% if hyperlipidemic) \200 <30% from all fats \200 50% as carbohydrate, which is mostly complex high \201 ber \200 Sodium content <6 g/day in most people or <3 g/day if hypertensive Alcohol is a signi \201 cant source of calories; reduced intake is advised in the overweight or hypertr iglyceridemic patient. The current \200\234standard \200\235 diet for a person with diabetes is a weight- reducin g low-fat, low \200\223glycemic index diet with reduced sodium content. Most patients will have type 2 diabetes and are slightly overweight, so this diet needs to be modi \201 ed to the individual. Oral hypoglycemic agents Sulfonylureas (Table 104.1) These agents are used as \201 rst-line treatment in non-obese patients with type 2 diabetes. The \201 rst-generation agents, chlorpropamide , tolbutam ide , and tolazamide, are rarely used today. Second-generation agents such as glibenclamide , gliclazide , and glipizide are more common ly used. Third-generation agents such as glimepiride are also available. Mode of action Sulfonylureas act by stimulating a receptor on the surface of B cells, clos- ing a potassium channel, and opening a calcium channel with subsequent Table 104.1 Properties of sulfonylureas Sulfonylurea Length of action Begins working within Daily dose (mg) Glibenclamide 16 \200\22324 hours 2 \200\2234 hours 2.5 \200\22315 Gliclazide 10 \200\22324 hours 2 \200\2234 hours 40 \200\223320 Glipizide 6 \200\22324 hours 2 \200\2234 hours 2.5 \200\22320 Chlorpropamide 24 \200\22372 hours 2 \200\2234 hours 100 \200\223500 Tolbutamide 6 \200\22310 hours 2 \200\2234 hours 500 \200\2232000 Glimepiride 12 \200\22324 hours 2 \200\2234 hours 1 \200\2236 104-Draznin-Chap104.indd 595 3/31/2011 4:47:45 PM CHAPTER 104 General management and treatment 596 insulin release. A doubling of glucose-stimulated insulin secretion can be expected with bo th \201 rst- and second-phase insulin secretion affected. This results in a 1 \200\2232% reduction in HbA1c over the long term. Side effects These are hypoglycemia and weight gain. The elderly are particularly at risk o f hypoglycemia with the longer-acting agents such as glibenclamide, and these should be avo ided in this age group. Occasional skin reactions, alterations in liver function tests, and minor GI symptoms may occur. Also avoid sulfonylureas in porphyria. Biguanides (Table 104.2) Metformin is \201 rst-line therapy in obese or overweight people with type 2 diabetes. It is also used in some insulin-treated, insulin-resistant, over- we ight subjects to reduce insulin requirements. The UK Prospective Diabetes Study (UKPDS) showed signi \201 cantly bet- ter results from m etformin for complications and mortality compared to other therapies in overweight patients with type 2 diabetes. Although a 1 \200\2232 kg weight loss is seen initially, UKPDS data suggest metformin does not signi \201 cantly alter weight over a 10-year period. Mode of action Metformin works by d hepatic gluconeogenesis and i muscle glucose uptake/met abolism, thus increasing insulin sensitivity. With long-term use a 0.8 \200\2232.0% reducti on in HbA1c can be expected. Side effects and contraindications Metformin is contraindicated in patients with renal (cre atinine >1.4), hepatic, or cardiac impairment or those who consume signi \201 cant amounts of alcohol. GI side effects include nausea, epigastric discomfort, and diarrhea and occur in up to 30% of patients in the \201 rst 1 \200\2232 weeks of treatment but are usually transient. If the starting dose is low (e.g., 500 mg once daily), most people develop a tolerance to thes e and are able to take higher doses; <5% are totally intolerant. Rarely, skin rashes may occur. When seen, they usually occur in patients with hepatic, renal, or cardiac impairment. Use of radiological contrast media with metformin is associated with an i risk of lactic ac idosis. Therapy should be stopped at the time of or prior to such investigations and restar ted 2 days after the test unless renal Table 104.2 Biguanides and prandial glucose regulators Length of action Begins working within Daily dose (mg) Drug Metformin 24 \200\22336 hours 2.5 hours 500 \200\2232000 Repaglinide 4 \200\2236 hours <1 hour 0.5 \200\22316 Nateglinide 4 hours <1 hour 180 \200\223540 104-Draznin-Chap104.indd 596 3/31/2011 4:47:45 PM ORAL HYPOGLYCEMIC AGENTS 597 function has been affected by the procedure, in which case this should be resolved \201 r st. Lactic acidosis occurs very infrequently, e.g., 0.024 \200\2230.15 cases/1000 patient years in a Swedish study. Although it is known to reduce folic acid and vitamin B 12 absorption, this is not usually a signi \201 cant problem clinically with metformin. Prandial glucose regulators (Table 104.2) These agents can be used in type 2 patients who h ave inadequate control on diet or metformin. They predominantly target postprandial hypergl yc- emia because of their short duration of action. Repaglinide, a carbamoylmethyl benzoic acid derivative, is a non- sulfonylurea oral hypogly cemic agent that stimulates the secretion of insulin from pancreatic B cells. It works on s eparate parts of the B-cell sulfonylurea receptor from the sulfonylureas. Its use results in an approximate 0.6 \200\2232% reduction in HbA1c levels. Its very short duration of action reduces the risk of hypoglycemia compared to that with some sulfonylurea s. It has an insulinotropic effect within 30 minutes of oral administration and a return to no rmal insulin levels within 4 \200\2236 hours (elimination half-life is around 1 hour). It s hould not, however, be used in patients with renal or hepatic impairment and may result in hepatic dysfunction, so periodic liver function test monitoring is required. Nateglinide is a D-phenylalanine derivative with an insulinotropic effect within 15 minutes of oral administration and a return to normal insulin levels by 2 hours (elimination half- life 1.5 hours), thus reducing the risk of subsequent hypoglycemia. Ef \201 cacy is simila r to that of repaglinide. A-glucosidase inhibitors (Table 104.3) These are used in type 2 p atients who have inadequate control on diet or other oral agents alone. When taken with foo d, acarbose reduces Table 104.3 Oral hypogylcemwic agents: summary Expected reduction in HbA1c (%) Class Mechanism of action Sulfonylureas Stimulate pancreatic insulin secretion 1.5 \200\2232.5 Biguanides Increase muscle glucose uptake and metabolism; decrease hepatic gluconeogenesis 0.8 \200\2232.0 Prandial glucose regulators A-Glucosidase inhibitors Stimulate pancreatic insulin secretion 0.5 \200\2231.9 Inhibit a digestive enzyme 0.4 \200\2230.7 Activate PPAR-G receptor Thiazolidinediones 0.6 \200\2231.5 104-Draznin-Chap104.indd 597 3/31/2011 4:47:45 PM CHAPTER 104 General management and treatment 598 postprandial glucose peaks by inhibiting the digestive enzyme A-glucosidase, which normally breaks carbohydrates into their monosaccharide compo- nents, thus retarding glucose uptake from the intestine and reducing post- prandial glucose peaks. Some improvement in lipids has also been reported. These undigested carbohydrates then pass into the large intestine where bacteria metabolize them. This may explain the common side effects of postprandial fullness or bloating, abdominal pain, \202 atulence, and diarrhea . Thiazolidinediones (Table 104.3) This class of drugs acts as insulin-sensitizing agents by activating the per- oxisome proliferator activated receptor (PPAR-G), which stimulates gene transcription for glucose transporter molecules such as Glut 1 and Glut 4. The \201 rst of this class was troglitazone, which was withdrawn soon after its launch because of report s of hepatotoxicity. Other agents, such as rosiglitazone and pioglitazone, are available, giving a 0.6 \200\2231 .5% drop in HbA1c. These do not seem to have the same problem with hepatotoxicity, and ther e is often an improvement in liver function, especially with nonalcoholic steatohepatitis ( NASH). Although the risk of hepatic dysfunction is not high, initial checks of liver function and monitoring of liver function test are still currently advised. In view of the more common p roblem with \202 uid retention, avoidance of use in patients with heart failure is also s trongly suggested. Recent studies suggest a link with osteoporosis with both the currently available agents. T he weight gain seen with both agents is also an impor- tant factor when considering the bes t therapy for any patient. Indications \200 Type 2 diabetes, oral combination with metformin or a sulfonylurea or a meglitinide Dose \200 Rosiglitazone 4 \200\2238 mg/day (combination metformin and rosiglitazone table ts are also available, either 2 mg or 4 mg rosiglitazone with 500 mg or 1 g metformin per t ablet) Pioglitazone 15 \200\22345 mg/day (combination metformin and pioglitazone as 15 mg pioglitazone and 850 mg metformin per tablet) Side effects \200 Fluid retention \200 Weight gain \200 Hepatotoxicity The incretin system (GLP-1 mimetics and DPP4 inhibitors) Glucagon-like polypeptide-1 (GLP-1 ) and gastric inhibitory polypeptide (GIP), also known as glucose-dependent insulinotropic peptide, are hor- mones made in the L- and K-cells of the jejunum and ileum in response to a food load entering the GI tract. These incretin hormones stimulate glucose-dependent insu lin secretion, suppress glucagon secretion, and slow gastric emptying, with an improvement in insulin sensitivity. 104-Draznin-Chap104.indd 598 3/31/2011 4:47:45 PM INSULIN 599 Exenatide is a GLP-1 mimetic. Dipeptidyl peptidase-4 (DPP-4) breaks down GIP and GLP-1. Thi s enzyme can be inhibited by oral drugs such as sitagliptin and vildagliptin (i.e., DPP-4 i nhibitors) with a resultant 0.4 \200\2230.7% reduction in HbA1c over a 12-month period. The y are weight neutral if not help in reducing weight. Liver monitoring with vildagliptin is currently recommended. The GLP-1 mimetic exenatide is available and is taken as a twice-daily injection of 5 mcg or 10 mcg per dose. It yields a 0.6 \200\2230.8% reduction in HbA1c after 30 weeks \200\231 use and a 1.6 \200\2232.8 kg w eight loss over the same period. Several depot preparations of GLP-1 analogs/mimetics are in develop- ment. Long-acting GLP-1analogs are coming to the market as well. Indications \200 Sitagliptin/vildagliptin \200\224type 2 diabetes, combination with metfo rmin or thiazolidinediones Exenatide \200\224type 2 diabetes, combination with metformin or sulfonylurea or both Dose \200 Sitagliptin 100 mg/day orally \200 Vildagliptin 100 mg/day orally \200 Exen atide 5 \200\22310 mcg twice daily by injection Side effects \200 Sitagliptin \200\224GI disturbance, upper respiratory tract infection, nasopharyngitis, peripheral edema Vildagliptin \200\224as sitagliptin + abnormal liver function tests \200 Exenatide GI upset with nausea, vomiting, abdominal distension, diarrhea \200 Headache, dizziness a nd increase sweating \200 Injection site reactions Insulin Insulin is required in all patients with type 1 diabetes and in some with type 2, f or the preservation of life; in other patients with type 2 diabetes it is needed to achieve better glycemic and metabolic control or for the relief of hyperglycemic symptoms (see Tab le 104.4 for detailed aims of treatment). Most insulin is in a biosynthetic human form (fro m yeast or bacteria) at a standard concentration: U100 (100 units/mL). Insulin can be given by IV or SC route. More recently, short-acting insulin was also given as an inhaled formulation, but this was withdrawn. Standard insulins come as 10 mL vials fo r use with a 0.5 mL or 1.0 mL syringe or as 3.0 mL cartridges for use in pen devices. The insulin itself is unmodi \201 ed/neutral or mixed with agents such as protamine or zin c to alter its onset of action, peak effect, and duration of action (see Table 104.5 for a summary of insulins). Analogs of human insulin to give more rapid onset or greater duration of action are also wi dely available and used. There are >30 types of insulin 104-Draznin-Chap104.indd 599 3/31/2011 4:47:45 PM CHAPTER 104 General management and treatment 600 Table 104.4 Suggested aims of treatment Fasting blood glucose <7 mmol/L HbA1c <7.2% (or <6.5% in those with signi \201 cant complications) Blood pressure <140/80 mmHg Body mass index 20 \200\22325 ideally Home monitoring Capillary blood glucose estimates taken fasting, pre- meal, 2 hours postprandially, and bef ore bed. These will need to be frequent enough to allow alterations in treatment and assess ment of adequate control. Often this monitoring 3 \227 week in stable type 2 patients and d aily in stable type 1 patients is adequate. Table 104.5 Insulin: summary Peak activity (h) Duration of action (h) Type of insulin Examples Insulin analog Humalog (insulin lispro) (NovoRapid ) Insulin Aspart 0 \200\2232 3 \200\2234 1 \200\2233 3 \200\2234 Human Actrapid Humulin R Short acting 1 \200\2233 2 \200\2233 6 \200\2238 6 \200\2238 Human Insulatard Humulin N Human Monotard Intermediate acting 2 \200\2238 2 \200\2238 3 \200\22312 10 \200\22316 10 \200\22316 18 \200\22324 Long acting Humulin Zn Human Ultratard 4 \200\2238 6 \200\22324 <24 <36 preparation available, which should allow full 24-hour cover for a wide variety of lifestyl es. The main problems with all insulin regimens are weight gain and hypogly- cemia. The latter condition occurring overnight can be troublesome, espe- cially as the patient may not know it has occurred and may react to the morning hyperglycemia by increasing their evening insu lin dose. Occasional checks of 3 A.M. blood glucose levels may help sort this out. Types of insulin Short-acting (soluble/neutral) insulins Humulin and Novolin are two r egular insulins that have an onset 30 minutes after injection, with a peak onset at 2 \200 \2234 hours, and a duration of up to 6 \200\2238 hours. They are rarely used now in the Uni ted States. 104-Draznin-Chap104.indd 600 3/31/2011 4:47:45 PM INSULIN 601 Insulin analogs Insulin lispro (Humalog ), insulin aspart (NovoRapid ), and insulin g lulisine (Apidra ) have been modi \201 ed to allow injecting and eating to occur simul - taneously. They have a more rapid onset of action and earlier peak effect with peak blood insulin levels approximately 1.5 \200\2232.5 times that from the same dose of regular huma n insulin. The duration of action is also shorter at 5 hours. This may cause prob- lems if there are long gaps between meals. Long-acting analogs, insulin g largine (Lantus ) and insulin d etemir (Levemir ), are also available. These have a \202 atter pro \201 le with a duration of action of 22 \200\22324 hours. They can be used as part of a basal bolus regimen with short-acting analo gs or regular insulins. They appear to have less hypoglycemia than other background insulins and may reduce the ris k of nocturnal hypoglycemia. Their use as a once- daily insulin alone or in combination wit h oral agents, such as glimepiride or the prandial glucose regulators, is also proving popu lar in the elderly type 2 patient. While insulin glargine has a slightly longer duration of action, making it a popular once-d aily preparation insulin detemir, because of its albumin- binding properties is reported to give less between-dose variability in the same individual. With a duration of action of 20 \200\22322 hours, it may be used in similar situations, although a signi \201 cant propor tion of people need to use this twice daily. Intermediate-acting (isophane) insulins Insulin action can be extended by addition of prota mine to give iso- phane insulin, with an onset of action 1 \200\2232 hours after injection, a peak at 4 \200\2236 hours, and duration of action of 8 \200\22314 hours. Different prepa rations have slightly different pro \201 les in terms of peak effect and maximal insulin c oncentrations, as with soluble preparations. Biphasic/mixed insulins Combinations of soluble/neutral or short-acting analogs with isopha ne insulins are extremely popular. The amount of soluble insulin present var- ies from 10 t o 50%, with 30% being the most popular. Depending on its monocomponents, onset is normally at 30 minutes, peak effect at 2 \200\223 6 hours, and duration 8 \200\22312 hours. Insulin analog biphasic prepara- tions have an on set, peak, and duration all slightly shorter than these. Insulin regimens Twice-daily free mixing Historically, these were very popular, although no w they are used less. The usual starting regimen was 2/3 isophane, 1/3 soluble, and 2/3 of the total daily dose was given pre-breakfast and 1/3 before the evening meal. The main prob lems are mixing them and pre-lunch hypo- or hyper- glycemia. If on the same doses twice dai ly, watch for pre-evening meal hyperglycemia and increase the morning isophane dose to comp ensate for this. A reduction in the morning soluble is often needed to reduce pre-lunch hyp oglycemia. 104-Draznin-Chap104.indd 601 3/31/2011 4:47:46 PM CHAPTER 104 General management and treatment 602 Twice-daily \201 xed mixture This is most commonly a 30% soluble/70% isophane mixture. Al though this is not ideal for pre-lunch control or alterations in diet and exercise that are not preplanned, it is indicated in type 2 patients with poor control, those with signi \201 cant osmotic symptoms, and those in whom there is no room to increase oral agents. A suitable starting regimen is a 30/70 mixture with 2/3 pre-breakfast and 1/3 pre-evening m eal. The exact doses tend to vary widely depending on insulin sensitivity, but a reasonable starting regimen may be 10 \200\22315 units pre-breakfast and 5 \200\22310 units pre-eveni ng meal. Basal bolus regimen This is regular insulin (rarely) or an insulin analog given 3 \227 day pre-meal with a pre-bed isophane or long-acting analog. It may have more \202 exibility with meal times, portions, and exercise than that of previous regimens. The larger number o f injections and more frequent capillary blood glucose measurements needed make it less pop ular with some patients. If starting this as the \201 rst type of insulin, 3 equal pre-meal doses should be given and altered as required, e.g., 4 \200\2236 units is a reasonable starting dose, with 6 \200 \2238 units of isophane pre-bed. If converting to a basal bolus regimen from a twice-daily biphasic regimen, the total daily insulin dose needs to be reduced by up to 10%. Initially, 30 \200\22350% of the total daily insulin needed is given as a pre-bed- time iso phane or long-acting analog and split the remaining insulin evenly between meals as soluble or short-acting analog insulin. Once the patient is on this regimen, the evening isophane or analog often needs to be increased to maintain adequate fasting sugars. In patients using short-acting insulin analogs and, less often, those on standard soluble i nsulins, a 2 \227 daily isophane or a long-acting analog is occasionally needed, especiall y if there is a long gap between lunch and the evening meal. Continuous SC insulin infusion (CSII) Insulin pumps are used infrequently in patients with type 1 DM. Potential problems are pump failure, ketoacidosis, and cannula site infections, although with improvements in technology these are less common prob- lems. Intensive diabet es education is a must. Insulin and oral agent mixtures In type 2 patients, several combinations are occasionally u sed. The two most popular ones are bedtime insulin + daytime tablets, and more fre- quent i nsulin + metformin. In the \201 rst mixture, oral agents continue during the day with a pre-bed isophane or l ong-acting insulin analog used to give acceptable fasting sugar levels pre-breakfast. Altho ugh patients often start at 10 units/night, doses 5 \200\2236 times that are not infrequent ly needed. In the second regimen, up to 2 g/day of metformin is added to any stand- ard insulin regime n in order to reduce insulin requirements and improve control without the problem of furthe r weight gain often seen if the insulin is continually increased. 104-Draznin-Chap104.indd 602 3/31/2011 4:47:46 PM INSULIN 603 Further reading Alberti KGMM, Gries FA, et al. (1994). A desktop guide for the management o f non-insulin depend- ent diabetes mellitus (NIDDM): an update. Diabet Med 11:899 \200\2239 09. American Diabetes Association (1994). ADA position statement. Nutrition recommendations and principles for people with diabetes mellitus. Diabet Car e 17:519 \200\223522. Bailey CJ, Day C, Campbell IW (2006). A consensus algorithm for treating hyperglycaemia in type 2 diabetes. Br J Diabet Vasc Dis 6(4):147 \200\223148. Bailey CJ, Turner RC (1996). Metformin. N Engl J Med 334:574 \200\223579. Campbell IW (1990). Ef \201 cacy and limitations of sulphonylurea and metformin. In Bailey CJ, Flatt PR, (Eds). New Antidiabetic Drugs . Nishimura, Japan: Smith-Gordon, pp. 33 \200 \22351. Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes (1 995). Recommendations for the nutritional management of patients with diabetes mellitus. Di abet Nutrit Metab 8(3):186 \200\223189. Nissen SE, Wolski K (2007). Effect of rosiglitazone on the risk of myocardial infarction an d death from cardiovascular causes. N Engl J Med 356(24):2457 \200\22371. Erratum in N Engl J Med 357(1):100. Ratner RE (1995). Rational insulin management of insulin-dependent diabetes. In Leslie RDG, Robbins DE (Eds) Diabetes: Clinical Science in Practice. Cambridge, UK: Cambridge Universi ty Press, pp. 434 \200\223449. STOP-NIDDM Trial (2003). Acabose treatment and the risk of cardiovascular disease and hyper - tension in patients with impaired glucose tolerance. JAMA 290:486 \200\223494. UK Prospective Diabetes Study (UKPDS) Group (1998). Intensive blood-glucose control with su l- fonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 352:837 \200\223853. UK Prospective Diabetes Study (UKPDS) Group (1998). Effect of intensive blood-glucose contr ol with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854 \200\223865. 104-Draznin-Chap104.indd 603 3/31/2011 4:47:46 PM CHAPTER 105 Diabetic eye disease 604 Diabetic eye disease Epidemiology Diabetic retinopathy remains the most common cause of blindness in the working population of developed countries. Currently, diabetic eye dis- ease gives a person with d iabetes a 10- to 20-fold i risk of blindness. It is suggested that 84,000 of the 7.8 millio n North American patients with dia- betics will develop proliferative retinopathy each year and another 95,000 will develop macular edema. The prevalence of diabetic retinopathy depends on the duration of diabetes, glycemic contro l, BP control, and the racial mix of the group being examined. A prevalence of 730% in a ge neral diabetic population is often quoted. In type 1 patients, <2% have any lesions of diabetic retinopathy at diag- nosis and only 8% have any features of it by 5 years (2% proliferative). But 87 \200\22398% have abnormaliti es 30 years later, 30% of these having had proliferative retinopathy. In type 2 patients, 2 0 \200\22337% can be expected to have retinopathy at diagnosis; 15 years later, 85% of thos e on insulin and 60% of those not taking insulin will have abnormalities. The 4-year incidence for proliferative retinopathy in a large North American epidemiologica l study was 10.5% in type 1 patients, 7.4% in older-onset/type 2 patients on insulin, and 2 .3% in those not on insulin. In the US, currently maculopathy is a more common and thus mor e sig- ni \201 cant sight-threatening complication of diabetes. It is suggested that 75% o f those with maculopathy have type 2 diabetes, and there is a 4-year inci- dence of 10.4% i n this group. Although type 2 patients are 10 times more likely to have maculopathy than ty pe 1 patients, 14% of type 1 patients who become blind do so because of maculopathy. Diabetic retinopathy, like many microvascular complications, is more common in ethnic minor ities than in Caucasians. Cataracts are more common in people with diabetes and are actuall y the most common eye abnormality found. These occur in up to 60% of 30- to 54-year-olds. Other abnormalities to look for include vitreous changes such as aster- oid hyalosis, which occur in about 2% of patients. These are small spheres or star-shaped opacities seen in th e vitreous that appear to sparkle when illuminated under an examining light and do not norm ally affect vision. b See Box 105.1 for classi \201 cation. 105-Draznin-Chap105.indd 604 3/31/2011 5:28:11 PM CLINICAL FEATURES AND HISTOLOGICAL FEATURES 605 Box 105.1 Classi \201 cation and features of diabetic retinopathy Background retinopathy \200 Microaneurysms \200 Hemorrhages \200 Hard exudates Preproliferative retinopathy \200 Soft exudates/cotton wool spots \200 Intraretinal abn ormalities (IRMAs) \200 Venous abnormalities (e.g., venous beading, looping, and reduplic ation) Proliferative retinopathy \200 New vessels on the disc or within 1 disc diameter of it (N VD) \200 New vessels elsewhere (NVE) \200 Rubeosis iridis ( neovascular glaucoma) Maculopathy (graded as M0 if none and M1 if present) \200 Hemorrhages and hard exudates i n the macula area \200 Reduced visual acuity with no abnormality seen Clinical features and histological features The classi \201 cation of diabetic retinopathy is based on ophthalmoscopic examination or retinal photographs. Several other changes not seen mac- roscopically may also explain some of these clinical \201 ndings. One of the \201 rst histological changes seen is thickening of the capillary basement mem brane and loss of the pericytes embedded in it. Both have been linked to hyperglycemia in e xperimental models; sorbitol accumula- tion and advanced glycation both have a role. In normal retinal capillaries there is a 1:1 relationship between endothelial cells and per icytes. Pericytes may control endothelial cell proliferation, main- tain the structural int egrity of capillaries, and regulate blood \202 ow. Altering these roles, along with the i blood viscosity, abnormal \201 brinolytic activity, and reduced red cell deformity also seen in diabetes, may lead to capillary occlusion, tissue hypoxia, and the stimulus for new vessel formation. Exactly how locally produced growth factors, altered protein kinase C, alterations in oxida tive stress responses, and alterations in the autoregu- lation of retinal blood \202 ow c ombine to cause this remains unclear. The natural progression is from background to preproliferative then to pro- liferative reti nopathy/maculopathy and, ultimately, sight-threatening disease. Background retinopathy Capillary microaneurysms are the earliest feature seen clinically, a s red dots. Small intraretinal hemorrhages, or \200\234blots, \200\235 also occur, as can hemorrhage 105-Draznin-Chap105.indd 605 3/31/2011 5:28:11 PM CHAPTER 105 Diabetic eye disease 606 into the nerve \201 ber layer, which are often more \202 ame shaped. With i capil- lary leakage, hard exudates, which are lipid deposits, can also be seen. Preproliferative retinopathy A cotton wool spot is an infarct in the nerve \201 ber layer that alters axoplas- mic transportation in ganglion cell neurons, giving an edematous infa rct seen as a pale gray, fuzzy-edged lesion, which gives it its name. IRMAs are tortu- ous dilated hypercellular capillaries in the retina that occur in response to retinal ischemia. A further change seen is alternating dilatation and constriction of veins (venous beading) as well as other venous alterations such as duplication and loop formation. Overall, there are large areas of capillary non-per- fusion occurring in the absence of new vessels. The Early Treatment of Diabetic Retinopathy Study (ETDRS) suggested that certain of these features matter and suggested a 4 \200\2232 \200\2231 rule: \200 4 quadrants of severe hemorrhages or microaneurysms \200 2 quadrants of IRMAs \200 1 quad rant with venous beading If the patient has one of these features, there is a 15% risk of d eveloping sight-threatening retinopathy within the next year; if two are present, the risk rises to 45%. Proliferative retinopathy New vessels are formed from the retina and can grow along, into, or out from it. A scaffolding for \201 brosis then forms. There are two forms of new vess els: those on the disc or within 1 disc diameter of the disc (NVD) and new vessels elsewher e (NVE). Both give no symptoms but can cause the problems of advanced retin- opathy, such as hemorrh age, scar tissue formation, traction on the retina, and retinal detachment, which actually results in loss of vision. Thus pan- retinal photocoagulation, which can result in the regr ession of these new vessels, is used when such problems are seen.