Biosynthesis

The human insulin gene resides on the short arm of chromosome 11. A unique set of transcription factors found in the β cell nucleus activates the transcription of the preproinsulin mRNA from the insulin gene, resulting preproinsulin, which then is cleaved to proinsulin by microsomal enzymes. Further, proinsulin is converted into insulin and a smaller connecting peptide, or C peptide, by proteolytic cleavage at two sites along the peptide chain, a process that takes place into the Golgi apparatus.

Biochemistry

Proinsulin consists of a single chain of 86 amino acids, which includes the A and B chains of the insulin molecule plus a connecting segment of 35 amino acids. The prohormone-converting enzymes type 1 and 2 recognize and cut at pairs of basic amino acids, thereby removing the intervening sequence. After the two pairs of basic amino acids are removed by carboxypeptidase E, the result is a 51 amino acid insulin molecule and a 31 amino acid residue, the C peptide. A small amount of proinsulin escapes cleavage and is secreted intact into the bloodstream, along with insulin and C peptide.

C peptide, the 31 amino acid peptide, released during cleavage of insulin from proinsulin in equimolar amounts with insulin, has no known biologic activity.

Insulin is a protein consisting of 51 amino acids contained within two peptide chains: an A chain, with 21 amino acids; and a B chain, with 30 amino acids. The chains are connected by two disulfide bridges. In addition, an intrachain disulfide bridge links positions 6 and 11 in the A chain. Endogenous insulin has a circulatory half-life of 3–5 min.

Secretion

The human pancreas secretes about 30 units of insulin per day into the portal circulation of normal adults in distinct pulses with a period of approximately 5 min. The basal concentration of insulin in the peripheral blood of fasting humans averages 10 μU/mL (0.4 ng/mL or 61 pmol/L). In normal control subjects, insulin seldom rises above 100 μU/mL (610 pmol/L) after standard meals. After ingestion of food, peripheral insulin concentration increases within 8–10 min, reaches peak concentrations by 30–45 min, and then rapidly declines to baseline values by 90–120 min postprandially.

Basal insulin secretion occurs in the absence of exogenous stimuli, in the fasting state. Plasma glucose levels below 80–100 mg/dL (4.4–5.6 mmol/L) do not stimulate insulin release. Stimulated insulin secretion occurs in response to exogenous stimuli. Glucose is the most potent stimulant of insulin release. The perfused pancreas releases insulin in two phases: when the glucose concentration increases suddenly, an initial short-lived burst of insulin release occurs (the first phase); if the glucose elevation persists, the insulin release gradually falls off and then begins to rise again to a steady level (the second phase). However, sustained levels of high glucose stimulation (≈4 h in vitro or >24 h in vivo) result in a reversible desensitization of the β-cell response to glucose but not to other stimuli.

The β-cell senses glucose through its metabolism. Glucose enters the pancreatic β cell by passive diffusion, facilitated by membrane proteins termed glucose transporters (GLUTs) (see later). The low-affinity enzyme glucokinase catalyzes the subsequent, and rate-limiting, step in glucose metabolism by the pancreatic β cell, the phosphorylation of glucose to glucose-6-phosphate. Glucose catabolism in the β cell causes a ↑ in the intracellular ATP-ADP ratio. Acting through the sulfonylurea receptor (SUR1), the nucleotide-sensing subunit of the ATP-sensitive potassium channels on the surface of the β cell, the rise in ATP:ADP ratio closes the potassium channels and depolarizes the cell, thereby activating the voltage-sensitive calcium channels and allowing the entry of calcium ions into the cell.

Insulin release requires calcium ion signaling. Some nonglucose stimuli of insulin release also function through increases in cytoplasmic Ca²⁺. The sulfonylurea and meglitinide (such as repaglinide) medications act by closing the ATP-sensitive potassium channels.

Glucose metabolism in the β cell also generates additional signals that amplify the secretory response to elevations in cytoplasmic Ca²⁺ concentration. The exact mechanisms of these amplifying signals remain unknown but involve multiple pathways and include increases in the intracellular signaling molecules diacylglycerol and cyclic adenosine monophosphate (cAMP).

Insulin Receptors and Insulin Action

Insulin action begins with the binding of insulin to a receptor on the surface of the target cell membrane. Most cells of the body have specific cell surface insulin receptors.

Metabolic Effects of Insulin

The major function of insulin is to promote storage of ingested nutrients.

Glucose Transporter Proteins

Glucose oxidation provides energy for most cells and is critical for brain function. Because cell membranes are impermeable to hydrophilic molecules such as glucose, all cells require carrier proteins to transport glucose across the lipid bilayers into the cytosol. Whereas the intestine and kidney have an energy-dependent Na⁺-glucose cotransporter, all other cells utilize non-energy-dependent transporters that facilitate diffusion of glucose from a higher concentration to a lower concentration across cell membranes. Facilitative glucose transporters comprise a large family including at least 13 members, with the first four members of the family (GLUT-1, GLUT-3, GLUT-2, and GLUT-4) being the best characterized. They have distinct affinities for glucose and distinct patterns of expression.

Biochemistry

Pancreatic α cells generates → the glucagon peptide from the large proglucagon peptide encoded by the preproglucagon gene located on human chromosome 2.

Secretion

In contrast to its stimulation of insulin secretion, glucose inhibits glucagon secretion. Conflicting data surround the question of whether glucose directly inhibits secretion from the α cell or whether it only acts via release of insulin and somatostatin from the β and δ cells, both of which inhibit the α cell directly.

Action of Glucagon

In contrast to insulin, glucagon signaling in the liver stimulates the breakdown of stored glycogen, maintains hepatic output of glucose from amino acid precursors (gluconeogenesis), and promotes hepatic output of ketone bodies from fatty acid precursors (ketogenesis). Glucagon facilitates the uptake of the gluconeogenic substrate alanine by liver and directs fatty acids away from re-esterification to TGs and toward ketogenic pathways.

⇒ glucagon signaling results in the net release of readily available energy stores from the liver in the form of glucose and ketones to the other tissues between meals.

Immune-Mediated Diabetes

Autoimmune destruction of β cells resulting in impaired insulin secretion has multiple genetic predispositions and is also related to environmental factors that are still poorly defined.

Type 1b Diabetes

Approximately, 5% of patients with the clinical features of type 1 DM lack serum evidence of autoimmunity. This probably represents a heterogeneous group of disorders that lead to profound β-cell destruction or loss, absolute insulin deficiency, and a syndrome clinically similar to autoimmune type 1a DM.

Etiology

Complex and multifactorial.

↔ often associated with a strong genetic predisposition or family history in first-degree relatives, more so than type 1 diabetes (however, the genetics of type 2 diabetes is poorly understood).

This form encompasses → individuals who have relative (rather than absolute) insulin deficiency and have peripheral IR.

At onset, most patients with type 2 DM do not require insulin to survive, but over time their insulin secretory capacity tends to deteriorate, and many, eventually need insulin treatment to achieve optimal glucose control.

Diabetic ketoacidosis (DKA) seldom occurs spontaneously in type 2 diabetes; when seen, it usually arises in association with the stress of another illness such as infection or with the use of certain drugs (e.g., corticosteroids and atypical antipsychotics). Although the pathogenesis is not fully understood, autoimmune destruction of β cells does not occur and patients do not have any of the other known causes of diabetes. The proposed pathways involved in the pathogenesis of type 2 DM are detailed in the (Fig. 8.1).

Obesity and Insulin Resistance in Type 2 DM

Most but not all patients with type 2 diabetes are overweight or obese or, those who are of normal weight by traditional weight criteria, may have an increased abdominal visceral distribution of fat. Excess weight itself causes some degree of IR. Increases in visceral adiposity correlate with increased IR. Both the tissue resistance to insulin and the impaired β-cell response to glucose appear to be further aggravated by sustained hyperglycemia, which may impede both insulin signaling and β-cell function (Fig. 8.1). Whereas patients with type 2 diabetes may have insulin levels that appear normal or elevated, the higher blood glucose levels in these patients would be expected to result in even higher insulin values had their β-cell function been normal. Thus, insulin secretion is defective in these patients and insufficient to compensate for IR and this progressive decline in β cell capacity leads to worsening of hyperglycemia over time. An increase in insulin levels with normal plasma glucose indicates IR. Abnormalities of insulin receptors—in concentrations, affinity, or both—affect insulin action. Target tissues downregulate the number of insulin receptors on the cell surface in response to chronically elevated circulating insulin levels, probably by increased intracellular degradation. Conditions associated with high insulin levels and lowered insulin binding to the receptor include obesity, high intake of carbohydrates, chronic exogenous overinsulinization.

Adipokines, Free Fatty Acids and Ectopic Lipid Storage

Adipose tissue can affect the insulin sensitivity of other tissues through the secretion of signaling molecules, adipokines, that inhibit (tumor necrosis factor α [TNF-α], interleukin [IL-6], leptin, resistin, etc.) or enhance (adiponectin) insulin signaling locally or in distal target tissues (Fig. 8.1). Levels of fat storage in adipocytes, along with insulin signaling itself, regulate the production and secretion of many of the adipokines. The release of FFAs by engorged adipocytes, especially visceral adipocytes, may play a role in the development of IR as well. Oxidation of FFAs by muscle and other tissues could inhibit glycolysis and reduce insulin-stimulated glucose removal (the Randle hypothesis). Increased fat storage in adipocytes and release of FFAs may also eventually cause a shift in lipid storage, increasing lipid uptake and storage in nonadipose tissues such as muscle, liver, and β cells. Ectopic lipid storage in these tissues may lead to a decrease in their insulin sensitivity.

Inflammation

Adipose tissue contains a variety of other cell type, besides adipocytes, including inflammatory/immune cells, such as macrophages and lymphocytes that appear to be implicated in obesity-induced IR, as well. The activated macrophages release TNF-α, IL-6, nitrix oxide, etc., that decrease the insulin sensitivity of the adipocytes and further increase their release of proinflammatory fatty acids and peptides, creating a positive feedback loop that maintains a chronic state of local inflammation and IR (Fig. 8.1). Release of these adipokines and proinflammatory cytokines, along with the increased release of FFA and the development of ectopic lipid accumulation, promotes the development of inflammation and IR in the other key insulin-target tissues, such as muscle and liver. Similar mechanisms could also lead to inflammation in the islets and contributes to β-cell failure. On the other hand, peroxisome proliferator activated receptor (PPAR)-γ, highly expressed in the adipose tissue, has beneficial effects on systemic insulin signaling.

Β-cell Defects in Type 2 DM

Although the majority of people with type 2 DM have IR, most people with IR do not have DM because their β cells compensate for the IR by producing and secreting more insulin. Those individuals who develop type 2 DM have a defect in the compensatory response of their β cells to IR. Functionally, this defect is revealed by a reduction in first phase insulin secretion and the maximal insulin secretion stimulation by glucose. While increased insulin secretion per cell may contribute to the compensatory response to IR, increases in the number of β cells play a role as well. In the setting of obesity, hyperplasia of pancreatic β cells is often present and probably accounts for the normal or exaggerated insulin response to the glucose and other stimuli seen in obese individuals without type 2 DM. Several possible defects contribute to the failure of cell mass compensation in people with type 2DM. In susceptible individuals with obesity, ectopic fat deposition in the islets, local obesity-induced inflammation in the islet and local and circulating adipokines and inflammatory cytokines may accelerate β-cell loss. As β-cell failure progresses, levels of glucose and FFA start to rise, which in turn can cause further β-cell toxicity. Once DM is established, all of these mechanisms may further contribute to the progressive decline in cell function that characterizes type 2 DM.

Genetics of Type 2 DM

Environmental Factors in Type 2 DM

Besides genetics, environment also plays a critical role in type 2 DM: it determines the age of the onset of the disease as well as its severity. The risk of developing type 2 DM is known to increase with age, obesity, and lack of physical activity. The prevalence of this disease is higher in Western countries and westernizing countries in comparison to underdeveloped countries. The higher the rates of obesity, the more increased the incidence of type 2 DM worldwide, indicating that people have more and more access to food with high caloric intake and lack physical activity, which ↑ adiposity, especially in the more readily mobilized fat stores surrounding the viscera in the abdomen. This increased visceral adiposity also accounts for the dramatic growing incidence of type 2 DM in children.

Maturity Onset Diabetes of the Young

MODY, the commonest cause of monogenic β-cell dysfunction, is estimated to be the underlying cause in 0.5–1% of all patients with diabetes. A typical ‘MODY patient’ has young age of onset (<45 years, frequently <25 years) and has diabetes not characteristic of type 1 or type 2 as well as a family history of diabetes that occurs in successive generations. MODY is characterized by impaired insulin secretion with minimal or no defects in insulin action (in the absence of coexistent obesity) and absence of autoimmune markers. It is inherited in an autosomal dominant pattern with abnormalities in at least 13 genes on different chromosomes identified to date. The most commonly reported forms are GCK-MODY (MODY2) (← heterozygous mutations in gene encoding the enzyme glucokinase), HNF1A-MODY (MODY3) (← heterozygous mutations in gene encoding the nuclear transcription factors hepatocyte nuclear factor 1A), and HNF4A-MODY (MODY1) (← heterozygous mutations in gene encoding the hepatocyte nuclear factor 4A).

Neonatal Diabetes

Diabetes occurring under 6 months of age is termed “neonatal” or “congenital” diabetes, and about 80–85% of cases can be found to have an underlying monogenic cause. Neonatal diabetes occurs much less often after 6 months of age, whereas autoimmune type 1 diabetes rarely occurs before 6 months of age. Neonatal diabetes can be either transient or permanent. Transient diabetes is most often due to overexpression of genes on chromosome 6q24, usually remits within 3 months, is recurrent in about half of cases, and may be treatable with medications other than insulin. Permanent neonatal diabetes is most commonly due to autosomal dominant mutations in the genes encoding the Kir6.2 subunit (KCNJ11) and SUR1 subunit (ABCC8) of the β-cell KATP channel. Correct diagnosis has critical implications because most patients with KATP-related neonatal diabetes will exhibit improved glycemic control when treated with high-dose oral sulfonylureas instead of insulin. Insulin gene mutations are the second most common cause of permanent neonatal diabetes (10–15% cases), and, while treatment presently is intensive insulin management or insulin sensitizers, there are important genetic considerations, as most of the mutations that cause diabetes are dominantly inherited.

Note: Refer those diagnosed before 6 months for genetic investigation, even if many years later and attending adult clinics → diagnosis could change management.

Mitochondrial Diabetes

Pregnancy in Women with Preexisting Diabetes

The risk assessment for GDM should be performed at the first prenatal visit (Table 8.4). Those women at high risk should undergo OGTT testing as soon as feasible. If the test is negative, then they should be retested at 24–28 weeks of gestation. Lower risk women are screened for GDM using a two-step protocol performed at 24–28 weeks (not detailed here).

Diagnosis of Gestational Diabetes

Dietary/Lifestyle Advice

Eating Patterns and Macronutrient Distribution

Metabolic surgery should be recommended as an option to treat type 2 diabetes in appropriate surgical candidates with BMI ≥ 40 kg/m² (BMI ≥ 37.5 kg/m² in Asian Americans), regardless of the level of glycemic control or complexity of glucose-lowering regimens, and in adults with BMI 35.0–39.9 kg/m² (32.5–37.4 kg/m² in Asian Americans) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.

Metabolic surgery should be considered as an option for adults with type 2 diabetes and BMI 30.0–34.9 kg/m² (27.5–32.4 kg/m² in Asian Americans) if hyperglycemia is inadequately controlled despite optimal medical control by either oral or injectable medications (including insulin).